Indole derivatives as selective androgen receptor modulators (SARMS)

ABSTRACT

The present invention is directed to novel indole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application Ser. No.11/096,740, filed on Apr. 1, 2005, now on U.S. Pat. No. 7,427,682 whichclaims the benefit of U.S. Provisional Application Ser. No. 60/567,717,filed on May 3, 2004, which is incorporated by reference herein in itsentirety.

FIELD OF THE INVENTION

The present invention is directed to novel indole derivatives,pharmaceutical compositions containing them and their use in thetreatment of disorders and conditions modulated by the androgenreceptor. More particularly, the compounds of the present invention areuseful in the treatment of prostate carcinoma, benign prostatichyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer,acne, AIDS, cachexia, as a male contraceptive, and/or as a maleperformance enhancer.

BACKGROUND OF THE INVENTION

Androgens are the anabolic steroid hormones of animals, controllingmuscle and skeletal mass, the maturation of the reproductive system, thedevelopment of secondary sexual characteristics and the maintenance offertility in the male. In women, testosterone is converted to estrogenin most target tissues, but androgens themselves may play a role innormal female physiology, for example, in the brain. The chief androgenfound in serum is testosterone, and this is the effective compound intissues such as the testes and pituitary. In prostate and skin,testosterone is converted to dihydrotestosterone (DHT) by the action of5α-reductase. DHT is a more potent androgen than testosterone because itbinds more strongly to the androgen receptor.

Like all steroid hormones, androgens bind to a specific receptor insidethe cells of target tissues, in this case the androgen receptor. This isa member of the nuclear receptor transcription factor family. Binding ofandrogen to the receptor activates it and causes it to bind to DNAbinding sites adjacent to target genes. From there it interacts withcoactivator proteins and basic transcription factors to regulate theexpression of the gene. Thus, via its receptor, androgens cause changesin gene expression in cells. These changes ultimately have consequenceson the metabolic output, differentiation or proliferation of the cellthat are visible in the physiology of the target tissue.

Although modulators of androgen receptor function have been employedclinically for some time, both the steroidal (Basaria, S., Wahlstrom, J.T., Dobs, A. S., J. Clin Endocrinol Metab (2001), 86, pp 5108-5117;Shahidi, N. T., Clin Therapeutics, (2001), 23, pp 1355-1390), andnon-steroidal (Newling, D. W., Br. J. Urol., 1996, 77 (6), pp 776-784)compounds have significant liabilities related to their pharmacologicalparameters, including gynecomastia, breast tenderness andhepatotoxicity. In addition, drug-drug interactions have been observedin patients receiving anticoagulation therapy using coumarins. Finally,patients with aniline sensitivities could be compromised by themetabolites of non-steroidal antiandrogens.

Non-steroidal agonists and antagonists of the androgen receptor areuseful in the treatment of a variety of disorders and diseases. Moreparticularly, agonists of the androgen receptor could be employed in thetreatment of prostate cancer, benign prostatic hyperplasia, hirsutism inwomen, alopecia, anorexia nervosa, breast cancer and acne. Antagonistsof the androgen receptor could be employed in male contraception, maleperformance enhancement, as well as in the treatment of cancer, AIDS,cachexia, and other disorders.

Nonetheless, there exists a need for small molecule, non-steroidalantagonists of the androgen receptor. We now describe a novel series ofindole derivatives as androgen receptor modulators.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of formula (I)

X is selected from the group consisting of O, S and NR¹;

R¹ is selected from the group consisting of hydrogen, lower alkyl,fluorinated lower alkyl, —SO₂-(lower alkyl), —SO₂-phenyl, —SO₂-tolyl,—(CH₂)-(fluorinated lower alkyl), -(lower alkyl)-CN, -(loweralkyl)-C(O)—O-(lower alkyl), -(lower alkyl)-O-(lower alkyl) and -(loweralkyl)-S(O)₀₋₂-(lower alkyl);

R⁴ is selected from the group consisting of hydrogen, halogen, loweralkyl, lower alkenyl, lower alkynyl and cyano; wherein the lower alkyl,lower alkenyl or lower alkynyl is optionally substituted on the terminalcarbon atom with —Si(lower alkyl)₃;

a is an integer from 0 to 4;

R⁵ is selected from the group consisting halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, halogensubstituted lower alkoxy, cyano, nitro, amino, lower alkylamino,di(lower alkyl)amino, —C(O)-(lower alkyl), —C(O)-(lower alkoxy),—C(O)—N(R^(A))₂, —S(O)₀₋₂-(lower alkyl), —SO₂—N(R^(A))₂,—N(R^(A))—C(O)-(lower alkyl), —N(R^(A))—C(O)-(halogen substituted loweralkyl) and aryl;

wherein each R^(A) is independently selected from hydrogen or loweralkyl;

wherein the aryl is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, carboxy, lower alkyl,halogen substituted lower alkyl, lower alkoxy, halogen substituted loweralkoxy, cyano, nitro, amino, lower alkylamino or di(lower alkyl)amino;

b is an integer from 0 to 1;

c is an integer from 0 to 1;

R⁷ is selected from the group consisting of hydrogen, lower alkyl and—Si(lower alkyl)₃;

R² is selected from the group consisting of hydrogen, lower alkyl,halogen substituted lower alkyl and —(CH₂)₁₋₄—Z—R⁶;

R³ is selected from the group consisting of lower alkyl, halogensubstituted lower alkyl and —(CH₂)₁₋₄—Z—R⁶;

wherein each Z is independently selected from the group consisting of—S(O)₀₋₂—, —O—, —O—C(O)—, —NH— and —N(lower alkyl)-;

wherein each R⁶ is independently selected from the group consisting oflower alkyl, halogen substituted lower alkyl, lower alkenyl, aryl,aralkyl, biphenyl, cycloalkyl, cycloalkyl-(lower alkyl), heteroaryl andheteroaryl-(lower alkyl);

wherein the cycloalkyl, aryl or heteroaryl group, whether alone or aspart of a substituent group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, cyano,nitro, amino, lower alkylamino, di(lower alkyl)amino, —S(O)₀₋₂-(loweralkyl) and —SO₂—N(R^(A))₂;

provided that when Z is O, NH or N(lower alkyl) then R⁶ is other thanlower alkenyl;

provided further that when R² is methyl, than R³ is other than methyl;

provided further that when X is NR¹, R¹ is hydrogen or lower alkyl, b is1, c is 0, R⁴ is hydrogen, R⁷ is hydrogen, a is 0 (R⁵ is absent) and R²is CF₃, then R³ is other than CF₃;

provided further that when X is NH, R⁴ is methyl, b is 0, c is 0, R⁷ ishydrogen, a is 0 (R⁵ is absent) and R² is methyl, then R³ is other thanCF₃;

provided further that when X is NR¹, R¹ is hydrogen or lower alkyl, R⁴is hydrogen or methyl, b is 0, c is 0, R⁷ is hydrogen, a is 0 (R⁵ isabsent) and R² is hydrogen or methyl, then R³ is other than—(CH₂)₁₋₂—N(R^(A))-(lower alkyl) or —(CH₂)₃—N(R^(A))-(benzyl);

provided further that when X is NH, R⁴ is hydrogen, b is 1, c 0, R⁷ ishydrogen, a is 0 (R⁵ is absent) and R² is hydrogen, then R³ is otherthan —(CH₂)—NH-(lower alkyl);

provided further that when X is NH, R⁴ is hydrogen, a is 0 (R⁵ isabsent), R⁷ is hydrogen, b is 0, c is 0 and R² is CF₃, then R₃ is otherthan —CH₂—O—C(O)—CH₃;

provided further that when X is NH, R⁴ is hydrogen, a is 0 (R⁵ isabsent), R⁷ is hydrogen, b is 1, c is 1 and R² is hydrogen, then R₃ isother than —CH₂—O—C(O)—CH₃;

provided further that when X is NR¹, R¹ is hydrogen or methyl, R⁴ ishydrogen or methyl, b is 0, c is 0, a is 0 (R⁵ is absent), R⁷ ishydrogen and R² is hydrogen, then R³ is other than —CH₂—O-lower alkyl or—CH₂—O-benzyl;

provided further that when X is O, R⁴ is hydrogen, b is 0, c is 0, R⁷ ishydrogen and R² is hydrogen, then R³ is other than CH₂—O-phenyl, whereinthe phenyl is optionally substituted with one to two substituentsindependently selected from lower alkyl, hydroxy substituted loweralkyl, carboxy and —C(O)-(lower alkoxy);

or a pharmaceutically acceptable salt thereof.

The present invention is further directed to a compound of formula (II)

wherein

X is selected from the group consisting of O, S and NR¹;

R¹ is selected from the group consisting of hydrogen, lower alkyl,fluorinated lower alkyl, —SO₂-(lower alkyl), —SO₂-phenyl, —SO₂-tolyl,—(CH₂)— (fluorinated lower alkyl), -(lower alkyl)-CN, -(loweralkyl)-C(O)—O-(lower alkyl), -(lower alkyl)-O-(lower alkyl) and -(loweralkyl)-S(O)₀₋₂-(lower alkyl);

R⁴ is selected from the group consisting of hydrogen, halogen, loweralkyl, lower alkenyl, lower alkynyl and cyano; wherein the lower alkyl,lower alkenyl or lower alkynyl is optionally substituted on the terminalcarbon atom with —Si(lower alkyl)₃;

a is an integer from 0 to 4;

R⁵ is selected from the group consisting halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, halogensubstituted lower alkoxy, cyano, nitro, amino, lower alkylamino,di(lower alkyl)amino, —C(O)-(lower alkyl), —C(O)-(lower alkoxy),—C(O)—N(R^(A))₂, —S(O)₀₋₂-(lower alkyl), —SO₂—N(R^(A))₂,—N(R^(A))—C(O)-(lower alkyl), —N(R^(A))—C(O)-(halogen substituted loweralkyl) and aryl;

wherein each R^(A) is independently selected from hydrogen or loweralkyl;

wherein the aryl is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, carboxy, lower alkyl,halogen substituted lower alkyl, lower alkoxy, halogen substituted loweralkoxy, cyano, nitro, amino, lower alkylamino or di(lower alkyl)amino;

b is an integer from 0 to 1;

c is an integer from 0 to 1;

R⁷ is selected from the group consisting of hydrogen, lower alkyl and—Si(lower alkyl)₃;

is a four to seven membered, saturated or partially unsaturated ringstructure (i.e. not an aromatic ring), containing one to two heteroatomsselected from O, N or S; wherein the four to seven membered, saturatedor partially unsaturated ring structure is optionally substituted with asubstituent selected from —(L¹)₀₋₁—R⁸;

wherein L¹ is selected from the group consisting of —(CH₂)₁₋₄—, —C(O)—,—C(O)—(CH₂)₁₋₄—, —C(O)O— and —C(O)O—(CH₂)₁₋₄;

wherein R⁸ is selected from the group consisting of aryl and heteroaryl;wherein the aryl or heteroaryl is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, hydroxy, carboxy, lower alkyl, halogen substituted lower alkyl,lower alkoxy, cyano, nitro, amino, lower alkylamino, di(loweralkyl)amino, —S(O)₀₋₂-(lower alkyl) and —SO₂—N(R^(A))₂;

provided that when X is NH or N(CH₃), R⁴ is hydrogen, b is 0, c is 0, R⁷is hydrogen or methyl and a is 0 (R⁵ is absent), then

is other than piperidinyl, wherein the piperidinyl is optionallysubstituted with lower alkyl or aralkyl;

or a pharmaceutically acceptable salt thereof.

The present invention is further directed to a compound of formula (III)

wherein

is a six membered heteroaryl ring structure containing one to twonitrogen atoms;

Y is NR¹;

R¹ is selected from the group consisting of hydrogen, lower alkyl,fluorinated lower alkyl, —SO₂-(lower alkyl), —SO₂-phenyl, —SO₂-tolyl,—(CH₂)-(fluorinated lower alkyl), -(lower alkyl)-CN, -(loweralkyl)-C(O)—O-(lower alkyl), -(lower alkyl)-O-(lower alkyl) and -(loweralkyl)-S(O)₀₋₂-(lower alkyl);

R⁴ is selected from the group consisting of hydrogen, halogen, loweralkyl, lower alkenyl, lower alkynyl and cyano; wherein the lower alkyl,lower alkenyl or lower alkynyl is optionally substituted on the terminalcarbon atom with —Si(lower alkyl)₃;

a is an integer from 0 to 4;

R⁵ is selected from the group consisting halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, halogensubstituted lower alkoxy, cyano, nitro, amino, lower alkylamino,di(lower alkyl)amino, —C(O)-(lower alkyl), —C(O)-(lower alkoxy),—C(O)—N(R^(A))₂, —S(O)₀₋₂-(lower alkyl), —SO₂—N(R^(A))₂,—N(R^(A))—C(O)-(lower alkyl), —N(R^(A))—C(O)-(halogen substituted loweralkyl) and aryl;

wherein each R^(A) is independently selected from hydrogen or loweralkyl;

wherein the aryl is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, carboxy, lower alkyl,halogen substituted lower alkyl, lower alkoxy, halogen substituted loweralkoxy, cyano, nitro, amino, lower alkylamino or di(lower alkyl)amino;

b is an integer from 0 to 1;

c is an integer from 0 to 1;

R⁷ is selected from the group consisting of hydrogen, lower alkyl and—Si(lower alkyl)₃;

R² is selected from the group consisting of hydrogen, lower alkyl,halogen substituted lower alkyl and —(CH₂)₁₋₄—Z—R⁶;

R³ is selected from the group consisting of lower alkyl, halogensubstituted lower alkyl and —(CH₂)₁₋₄—Z—R⁶;

wherein each Z is independently selected from the group consisting of—S(O)₀₋₂—, —O—, —O—C(O)—, —NH— and —N(lower alkyl)-;

wherein each R⁶ is independently selected from the group consisting oflower alkyl, halogen substituted lower alkyl lower alkenyl, aryl,aralkyl, biphenyl, cycloalkyl, cycloalkyl-(lower alkyl), heteroaryl andheteroaryl-(lower alkyl);

wherein the cycloalkyl, aryl or heteroaryl group, whether alone or aspart of a substituent group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, cyano,nitro, amino, lower alkylamino, di(lower alkyl)amino, —S(O)₀₋₂-(loweralkyl) and —SO₂—N(R^(A))₂;

provided that when Z is O, NH or N(lower alkyl) then R⁶ is other thanlower alkenyl;

or a pharmaceutically acceptable salt thereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedherein. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described herein and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described herein and a pharmaceutically acceptablecarrier.

Exemplifying the invention are methods of treating disorders andconditions modulated by the androgen receptor in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of any of the compounds or pharmaceutical compositionsdescribed herein.

An example of the invention is a method for treating an androgenreceptor modulated disorder selected from the group consisting ofprostate carcinoma, benign prostatic hyperplasia, hirsutism, or for malecontraception, in a subject in need thereof comprising administering tothe subject an effective amount of any of the compounds orpharmaceutical compositions described herein.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)prostate carcinoma, (b) benign prostatic hyperplasia, (c) hirsutism, (d)alopecia, (e) anorexia nervosa, (f) breast cancer, (g) acne, (h) AIDS,(i) cachexia, for (j) male contraception, or for (k) male performanceenhancement, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I), compoundsof formula (II) and compounds of formula (III)

wherein

a, b, c, X, Y, R², R³, R⁴, R⁵ and R⁷ are as herein defined, useful asselective androgen receptor modulators for the treatment of prostatecarcinoma, benign prostatic hyperplasia (BPH), hirsitutism, alopecia,anorexia nervosa, breast cancer, acne, AIDS, cachexia, as a malecontraceptive, and/or as a male performance enhancer.

In an embodiment, the present invention is directed to compounds offormula (I) wherein

X is selected from the group consisting of O, S and NR¹;

R¹ is selected from the group consisting of hydrogen, lower alkyl,fluorinated lower alkyl, —SO₂-(lower alkyl), —(CH₂)-(fluorinated loweralkyl), -(lower alkyl)-CN, -(lower alkyl)-C(O)—O-(lower alkyl), -(loweralkyl)-O-(lower alkyl) and -(lower alkyl)-S(O)₀₋₂-(lower alkyl);

R⁴ is selected from the group consisting of hydrogen, halogen, loweralkyl, lower alkenyl, lower alkynyl and cyano; wherein the lower alkyl,lower alkenyl or lower alkynyl is optionally substituted on the terminalcarbon atom with —Si(lower alkyl)₃;

a is an integer from 0 to 4;

R⁵ is selected from the group consisting halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, halogensubstituted lower alkoxy, cyano, nitro, amino, lower alkylamino,di(lower alkyl)amino, —C(O)-(lower alkyl), —C(O)-(lower alkoxy),—C(O)—N(R^(A))₂, —S(O)₀₋₂-(lower alkyl), —SO₂—N(R^(A))₂,—N(R^(A))—C(O)-(lower alkyl), —N(R^(A))—C(O)-(halogen substituted loweralkyl) and aryl;

wherein each R^(A) is independently selected from hydrogen or loweralkyl;

wherein the aryl is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, carboxy, lower alkyl,halogen substituted lower alkyl, lower alkoxy, halogen substituted loweralkoxy, cyano, nitro, amino, lower alkylamino or di(lower alkyl)amino;

b is an integer from 0 to 1;

c is an integer from 0 to 1;

R⁷ is selected from the group consisting of hydrogen, lower alkyl and—Si(lower alkyl)₃;

R² is selected from the group consisting of hydrogen, lower alkyl,halogen substituted lower alkyl and —(CH₂)₁₋₄—Z—R⁶;

R³ is selected from the group consisting of lower alkyl, halogensubstituted lower alkyl and —(CH₂)₁₋₄—Z—R⁶;

wherein each Z is independently selected from the group consisting of—S(O)₀₋₂—, —O—, —O—C(O)—, —NH— and —N(lower alkyl)-;

wherein each R⁶ is independently selected from the group consisting oflower alkyl, halogen substituted lower alkyl, lower alkenyl, aryl,aralkyl, biphenyl, cycloalkyl, cycloalkyl-(lower alkyl), heteroaryl andheteroaryl-(lower alkyl);

wherein the cycloalkyl, aryl or heteroaryl group, whether alone or aspart of a substituent group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, cyano,nitro, amino, lower alkylamino, di(lower alkyl)amino, —S(O)₀₋₂-(loweralkyl) and —SO₂—N(R^(A))₂;

and pharmaceutically acceptable salts thereof.

In an embodiment, the present invention is directed to compounds offormula (II) wherein

X is selected from the group consisting of O, S and NR¹;

R¹ is selected from the group consisting of hydrogen, lower alkyl,fluorinated lower alkyl, —SO₂-(lower alkyl), —(CH₂)-(fluorinated loweralkyl), -(lower alkyl)-CN, -(lower alkyl)-C(O)—O-(lower alkyl), -(loweralkyl)-O-(lower alkyl) and -(lower alkyl)-S(O)₀₋₂-(lower alkyl);

R⁴ is selected from the group consisting of hydrogen, halogen, loweralkyl, lower alkenyl, lower alkynyl and cyano; wherein the lower alkyl,lower alkenyl or lower alkynyl is optionally substituted on the terminalcarbon atom with —Si(lower alkyl)₃;

a is an integer from 0 to 4;

R⁵ is selected from the group consisting halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, halogensubstituted lower alkoxy, cyano, nitro, amino, lower alkylamino,di(lower alkyl)amino, —C(O)-(lower alkyl), —C(O)-(lower alkoxy),—C(O)—N(R^(A))₂, —S(O)₀₋₂-(lower alkyl), —SO₂—N(R^(A))₂,—N(R^(A))—C(O)-(lower alkyl), —N(R^(A))—C(O)-(halogen substituted loweralkyl) and aryl;

wherein each R^(A) is independently selected from hydrogen or loweralkyl;

wherein the aryl is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, carboxy, lower alkyl,halogen substituted lower alkyl, lower alkoxy, halogen substituted loweralkoxy, cyano, nitro, amino, lower alkylamino or di(lower alkyl)amino;

b is an integer from 0 to 1;

c is an integer from 0 to 1;

R⁷ is selected from the group consisting of hydrogen, lower alkyl and—Si(lower alkyl)₃;

is a four to seven membered saturated or partially unsaturated ringstructure, containing one to two heteroatoms selected from O, N or S;wherein the four to seven membered saturated or partially unsaturatedring structure is optionally substituted with a substituent selectedfrom —(L¹)₀₋₁—R⁸;

wherein L¹ is selected from the group consisting of —(CH₂)₁₋₄—, —C(O)—,—C(O)—(CH₂)₁₋₄—, —C(O)O— and —C(O)O—(CH₂)₁₋₄;

wherein R³ is selected from the group consisting of aryl and heteroaryl;wherein the aryl or heteroaryl is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, hydroxy, carboxy, lower alkyl, halogen substituted lower alkyl,lower alkoxy, cyano, nitro, amino, lower alkylamino, di(loweralkyl)amino, —S(O)₀₋₂-(lower alkyl) and —SO₂—N(R^(A))₂;

and pharmaceutically acceptable salts thereof.

In an embodiment, the present invention is directed to compounds offormula (III) wherein

is a six membered heteroaryl ring structure containing one to twonitrogen atoms;

Y is NR¹;

R¹ is selected from the group consisting of hydrogen, lower alkyl,fluorinated lower alkyl, —SO₂-(lower alkyl), —(CH₂)-(fluorinated loweralkyl), -(lower alkyl)-CN, -(lower alkyl)-C(O)—O-(lower alkyl), -(loweralkyl)-O-(lower alkyl) and -(lower alkyl)-S(O)₀₋₂-(lower alkyl);

R⁴ is selected from the group consisting of hydrogen, halogen, loweralkyl, lower alkenyl, lower alkynyl and cyano; wherein the lower alkyl,lower alkenyl or lower alkynyl is optionally substituted on the terminalcarbon atom with —Si(lower alkyl)₃;

a is an integer from 0 to 4;

R⁵ is selected from the group consisting halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, halogensubstituted lower alkoxy, cyano, nitro, amino, lower alkylamino,di(lower alkyl)amino, —C(O)-(lower alkyl), —C(O)-(lower alkoxy),—C(O)—N(R^(A))₂, —S(O)₀₋₂-(lower alkyl), —SO₂—N(R^(A))₂,—N(R^(A))—C(O)-(lower alkyl), —N(R^(A))—C(O)-(halogen substituted loweralkyl) and aryl;

wherein each R^(A) is independently selected from hydrogen or loweralkyl;

wherein the aryl is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, carboxy, lower alkyl,halogen substituted lower alkyl, lower alkoxy, halogen substituted loweralkoxy, cyano, nitro, amino, lower alkylamino or di(lower alkyl)amino;

b is an integer from 0 to 1;

c is an integer from 0 to 1;

R⁷ is selected from the group consisting of hydrogen, lower alkyl and—Si(lower alkyl)₃;

R² is selected from the group consisting of hydrogen, lower alkyl,halogen substituted lower alkyl and —(CH₂)₁₋₄—Z—R⁶;

R³ is selected from the group consisting of lower alkyl, halogensubstituted lower alkyl and —(CH₂)₁₋₄—Z—R⁶;

wherein each Z is independently selected from the group consisting of—S(O)₀₋₂—, —O—, —O—C(O)—, —NH— and —N(lower alkyl)-;

wherein each R⁶ is independently selected from the group consisting oflower alkyl, halogen substituted lower alkyl lower alkenyl, aryl,aralkyl, biphenyl, cycloalkyl, cycloalkyl-(lower alkyl), heteroaryl andheteroaryl-(lower alkyl);

wherein the cycloalkyl, aryl or heteroaryl group, whether alone or partof a substituent group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, cyano,nitro, amino, lower alkylamino, di(lower alkyl)amino, —S(O)₀₋₂-(loweralkyl) and —SO₂—N(R^(A))₂;

and pharmaceutically acceptable salts thereof.

In an embodiment of the present invention is a compound of formula (Ia)

i.e. a compound of formula (I) wherein b and c are each 0. In anembodiment of the present invention is a compound of formula (Ia)wherein R² is other than —(CH₂)₁₋₄—Z—R⁶. In another embodiment of thepresent invention is a compound of formula (Ia) wherein R³ is selectedfrom —(CH₂)₁₋₄—Z—R⁶.

In an embodiment of the present invention is a compound of formula (Ia)wherein R³ is —(CH₂)₁₋₄—S(O)₀₋₂—R⁶. In another embodiment of the presentinvention is a compound of formula (Ia) wherein R³ is selected from—(CH₂)₁₋₄—NH—R⁶. or —(CH₂)₁₋₄—N(lower alkyl)-R⁶. In yet anotherembodiment of the present invention is a compound of formula (Ia)wherein R³ is selected from —(CH₂)₁₋₄—O—R⁶. or —(CH₂)₁₋₄—O—C(O)—R⁶.

In an embodiment of the present invention

is pyridyl. In another embodiment of the present invention,

is selected from the group consisting of

Preferably,

is selected from the group consisting of

In another embodiment of the present invention,

is selected from the group consisting of

In an embodiment of the present invention is a compound of formula (III)wherein R³ is —(CH₂)₁₋₄—S(O)₀₋₂—R⁶. In another embodiment of the presentinvention is a compound of formula (III) wherein R³ is selected from—(CH₂)₁₋₄—NH—R⁶. or —(CH₂)₁₋₄—N(lower alkyl)-R⁶. In yet anotherembodiment of the present invention is a compound of formula (III)wherein R³ is selected from —(CH₂)₁₋₄—O—R⁶. or —(CH₂)₁₋₄—O—C(O)—R⁶.

In an embodiment of the present invention

is a four to seven membered saturated or partially unsaturated ringstructure, containing one to two heteroatoms selected from O, N or S;wherein the four to seven membered saturated or partially unsaturatedring structure is optionally substituted with a substituent selectedfrom —(L¹)₀₋₁—R⁸.

In an embodiment of the present invention L¹ is selected from the groupconsisting of —(CH₂)₁₋₄—, —C(O)— and —C(O)—(CH₂)₁₋₄—.

In an embodiment of the present invention R⁸ is selected from the groupconsisting of aryl and heteroaryl; wherein the aryl or heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, carboxy, loweralkyl, halogen substituted lower alkyl, lower alkoxy, cyano, nitro,amino, lower alkylamino, di(lower alkyl)amino, —S(O)₀₋₂-(lower alkyl)and —SO₂—N(R^(A))₂.

In an embodiment of the present invention

is selected from the group consisting of tetrahydro-thienyl,tetrahydro-thiopyranyl and piperidinyl.

In another embodiment of the present invention

is piperidinyl, wherein the piperidinyl is optionally substituted with agroup selected from aryl, aryl-carbonyl, aralkyl or aralkyl-carbonyl,and wherein the aryl or aralkyl substituent on the piperidinyl isoptionally substituted with one or more, preferably one to two, morepreferably one, substituent selected from the group consisting ofhalogen, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxyand lower alkyl-sulfonyl.

In yet another embodiment of the present invention

is piperidinyl, wherein the piperidinyl is optionally substituted with agroup selected from benzyl, fluoro-benzyl, chloro-benzyl,dichloro-benzyl, methyl-benzyl, methoxy-benzyl, trifluoromethyl-benzyl,t-butyl-benzyl, methylsulfonyl-benzyl, benzyloxy-carbonyl orchlorophenyl-carbonyl.

In an embodiment of the present invention a is an integer from 0 to 3.Preferably, a is an integer from 0 to 2. More preferably, a is aninteger from 1 to 2.

In an embodiment of the present invention b is 0 and c is 1. In anotherembodiment of the present invention b is 1 and c is 0. In yet anotherembodiment of the present invention b is 0 and c is 0.

In an embodiment of the present invention X is O or NR¹. Preferably, Xis NR¹.

In an embodiment of the present invention R¹ is selected from the groupconsisting of hydrogen, lower alkyl, fluorinated lower alkyl, -(loweralkyl)-CN, (lower alkyl)-O-(lower alkyl), (lower alkyl)-S(O)₀₋₂-(loweralkyl), —SO₂— (lower alkyl), —SO₂-phenyl and —SO₂-toyl.

In another embodiment of the present invention R¹ is selected from thegroup consisting of hydrogen, lower alkyl, fluorinated lower alkyl,-(lower alkyl)-CN, (lower alkyl)-O-(lower alkyl), (loweralkyl)-S(O)₀₋₂-(lower alkyl) and —SO₂-(lower alkyl).

In another embodiment of the present invention R¹ is selected from thegroup consisting of hydrogen, lower alkyl, halogenated lower alkyl,lower alkyl-sulfonyl, lower alkoxy-lower alkyl, cyano-lower alkyl andlower alkyl-thio-lower alkyl. Preferably, R¹ is selected from the groupconsisting of hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl,methyl-sulfonyl, methoxy-methyl, cyano-methyl and methyl-thio-methyl.

In an embodiment of the present invention R² is selected from the groupconsisting of hydrogen, lower alkyl, halogen substituted lower alkyl and—(CH₂)—Z—R⁶, wherein Z is selected from the group consisting of—S(O)₀₋₂—, preferably Z is —S—. Preferably R² is selected from the groupconsisting of hydrogen, methyl, ethyl, trifluoromethyl and —CH₂—S-ethyl.

In another embodiment of the present invention R² is selected from thegroup consisting of hydrogen and lower alkyl. Preferably, R² is selectedfrom the group consisting of hydrogen and methyl. More preferably, R² ismethyl. In another embodiment, R² is selected from the group consistingof hydrogen and trifluoromethyl.

In an embodiment of the present invention R³ is selected from the groupconsisting of lower alkyl, halogen substituted lower alkyl,—(CH₂)₀₋₂—Z—R⁶.

In another embodiment of the present invention R³ is selected from thegroup consisting of methyl, chloromethyl, trifluoromethyl,—CH₂—O-(4-cyanophenyl), —CH₂—O-(3-nitrophenyl),—CH₂-(3-trifluoromethyl-4-cyanophenyl), —S-methyl, —S-isopropyl,—S-cyclohexyl, —S-phenyl, —S-(4-chlorophenyl), —S-(4-fluorophenyl),—S-(3,4-dichlorophenyl), —S-(4-aminophenyl), —SO₂-(4-chlorophenyl),—SO₂-(3,4-dichlorophenyl), —CH₂—S-methyl, —CH₂—S-ethyl, —CH₂—S-butyl,—CH₂—S-propyl, —CH₂—S-isopropyl, —CH₂—S-isobutyl, —CH₂—S-allyl,—CH₂—S-phenyl, —CH₂—S-(2-chlorophenyl), —CH₂—S-(4-chlorophenyl),—CH₂—S-(4-fluorophenyl), —CH₂—S-(4-methoxyphenyl),—CH₂—S-(4-carboxyphenyl), —CH₂—S-(4-hydroxyphenyl),—CH₂—S-(4-nitrophenyl), —CH₂—S-(4-aminophenyl),—CH₂—S-(4-dimethylamino-phenyl), —CH₂—S-(3,4-dichlorophenyl),—CH₂—S-(2,2,2-trifluoroethyl), —CH₂—S-benzyl, —CH₂—S-cyclopentyl,—CH₂—S-cyclohexyl, —CH₂—S-(2-thienyl-methyl), —CH₂—S-(2-furyl-methyl),—CH₂—S-(2-pyridyl-methyl), —CH₂—SO-ethyl, —CH₂—SO-phenyl,—CH₂—SO-(3,4-dichlorophenyl), —CH₂—SO-(2,2,2-trifluoroethyl),—CH₂—SO-benzyl, —CH₂—SO₂-methyl, —CH₂—SO₂-ethyl, —CH₂—SO₂-propyl,—CH₂—SO₂-(4-fluorophenyl), —CH₂—SO₂-(4-hydroxyphenyl),—CH₂—SO₂-(4-aminophenyl), —CH₂—SO₂-(4-dimethylamino-phenyl),—CH₂—SO₂-(4-methoxyphenyl), —CH₂—SO₂-(2,2,2-trifluoroethyl),—CH₂—SO₂-benzyl, —CH₂CH₂—S-methyl, —CH₂CH₂—SO-methyl,—CH₂CH₂—SO₂-methyl, —CH₂—O—C(O)-(2-chlorophenyl),—CH₂—O—C(O)-(3-chlorophenyl), —CH₂—O—C(O)-(4-chlorophenyl),—CH₂—O—C(O)-(4-fluorophenyl), —CH₂—O—C(O)-(4-nitrophenyl),—CH₂—O—C(O)-(4-methyl-phenyl), —CH₂—O—C(O)-(4-methoxy-phenyl),—CH₂—O—C(O)-(2-trifluoro-methyl-phenyl), —CH₂—O—C(O)-(4-t-butyl-phenyl),—CH₂—O—C(O)-phenyl, —CH₂—O—C(O)-(3,4-dichloro-phenyl),—CH₂—O—C(O)-(2,6-dichloro-phenyl),—CH₂—O—C(O)-(4-dimethyl-amino-phenyl), —CH₂—O—C(O)-(4-biphenyl),—CH₂—O—C(O)-(2-pyridyl), —CH₂—O—C(O)-(3-pyridyl) and—CH₂—O—C(O)-(5-chloro-6-benzothienyl).

In another embodiment of the present invention R³ is selected from thegroup consisting of methyl, chloromethyl, trifluoromethyl, —S-methyl,—S-isopropyl, —S-cyclohexyl, —S-phenyl, —S-(4-chlorophenyl),—S-(4-fluorophenyl), —S-(3,4-dichlorophenyl), —S-(4-aminophenyl),—SO₂-(4-chlorophenyl), —SO₂-(3,4-dichlorophenyl), —CH₂—S-methyl,—CH₂—S-ethyl, —CH₂—S-butyl, —CH₂—S-propyl, —CH₂—S-isopropyl,—CH₂—S-isobutyl, —CH₂—S-allyl, —CH₂—S-phenyl, —CH₂—S-(2-chlorophenyl),—CH₂—S-(4-chlorophenyl), —CH₂—S-(4-fluorophenyl),—CH₂—S-(4-methoxyphenyl), —CH₂—S-(4-carboxyphenyl),—CH₂—S-(4-hydroxyphenyl), —CH₂—S-(4-nitrophenyl),—CH₂—S-(4-aminophenyl), —CH₂—S-(4-dimethylamino-phenyl),—CH₂—S-(3,4-dichlorophenyl), —CH₂—S-(2,2,2-trifluoroethyl),—CH₂—S-benzyl, —CH₂—S-cyclopentyl, —CH₂—S-cyclohexyl,—CH₂—S-(2-thienyl-methyl), —CH₂—S-(2-furyl-methyl),—CH₂—S-(2-pyridyl-methyl), —CH₂—SO-ethyl, —CH₂—SO-phenyl,—CH₂—SO-(3,4-dichlorophenyl), —CH₂—SO-(2,2,2-trifluoroethyl),—CH₂—SO-benzyl, —CH₂—SO₂-methyl, —CH₂—SO₂-ethyl, —CH₂—SO₂-propyl,—CH₂—SO₂-(4-fluorophenyl), —CH₂—SO₂-(4-hydroxyphenyl),—CH₂—SO₂-(4-aminophenyl), —CH₂—SO₂-(4-dimethylamino-phenyl),—CH₂—SO₂-(4-methoxyphenyl), —CH₂—SO₂-(2,2,2-trifluoroethyl),—CH₂—SO₂-benzyl, —CH₂CH₂—S-methyl, —CH₂CH₂—SO-methyl,—CH₂CH₂—SO₂-methyl, —CH₂—O—C(O)-(2-chlorophenyl),—CH₂—O—C(O)-(3-chlorophenyl), —CH₂—O—C(O)-(4-chlorophenyl),—CH₂—O—C(O)-(4-fluorophenyl), —CH₂—O—C(O)-(4-nitrophenyl),—CH₂—O—C(O)-(4-methyl-phenyl), —CH₂—O—C(O)-(4-methoxy-phenyl),—CH₂—O—C(O)-(2-trifluoro-methyl-phenyl), —CH₂—O—C(O)-(4-t-butyl-phenyl),—CH₂—O—C(O)-phenyl, —CH₂—O—C(O)-(3,4-dichloro-phenyl),—CH₂—O—C(O)-(2,6-dichloro-phenyl),—CH₂—O—C(O)-(4-dimethyl-amino-phenyl), —CH₂—O—C(O)-(4-biphenyl),—CH₂—O—C(O)-(2-pyridyl), —CH₂—O—C(O)-(3-pyridyl) and—CH₂—O—C(O)-(5-chloro-6-benzothienyl).

In another embodiment of the present invention R³ is selected from thegroup consisting of —CH₂—S(O)₀₋₂—R⁶, wherein R⁶ is selected from thegroup consisting of lower alkyl, halogen substituted lower alkyl, aryl,aralkyl, biphenyl, heteroaryl and heteroaryl-(lower alkyl); wherein thearyl or heteroaryl group, whether alone or as part of a substituentgroup is optionally substituted with one or more, preferably, one tothree, substituents independently selected from halogen, hydroxy,carboxy, lower alkyl, halogen substituted lower alkyl, lower alkoxy,cyano, nitro, amino, lower alkylamino, di(lower alkyl)amino,—S(O)₀₋₂-(lower alkyl) and —SO₂—N(R^(A))₂; and wherein each R^(A) isindependently selected from hydrogen or lower alkyl. Preferably, R³ isselected from the group consisting of —CH₂—S(O)₀₋₂-(lower alkyl), morepreferably, R³ is selected from the group consisting of —CH₂—S-(loweralkyl) and —CH₂—SO₂-(lower alkyl).

In an embodiment of the present invention Z is selected from the groupconsisting of —S(O)₀₋₂—, —O— and —O—C(O)—. In another embodiment of thepresent invention Z is selected from the group consisting of —S(O)₀₋₂—and —O—C(O)—. In another embodiment of the present invention Z isselected from the group consisting of —S—, —SO— and —SO₂—, preferably Zis selected from the group consisting of —S— and —SO₂—. In anotherembodiment of the present invention Z is selected from the groupconsisting of —NH— and —N(lower alkyl)-. In yet another embodiment ofthe present invention Z is selected from the group consisting of —O— and—O—C(O)—, preferably Z is —O—C(O)—.

In an embodiment of the present invention R⁶ is selected from the groupconsisting of lower alkyl, halogen substituted lower alkyl, loweralkenyl, cycloalkyl, aryl, aralkyl, biphenyl, heteroaryl andheteroaryl-(lower alkyl)-; wherein the aryl or heteroaryl, whether aloneor as part of a substituent group is optionally substituted with one ormore substituents independently selected from halogen, hydroxy, carboxy,cyano, nitro, amino, (lower alkyl)amino, di(lower alkyl)amino, loweralkyl, halogen substituted lower alkyl, lower alkoxy or —S(O)₀₋₂-(loweralkyl).

In another embodiment of the present invention, R⁶ is selected from thegroup consisting of lower alkyl, lower alkenyl, halogen substitutedlower alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and -(loweralkyl)-heteroaryl; wherein the aryl or heteroaryl, whether alone or aspart of a substituent group, is optionally substituted with one or more,preferably one to two, substituents independently selected from halogen,hydroxy, carboxy, nitro, amino, (lower alkyl)amino, di(loweralkyl)amino, lower alkyl, lower alkoxy, trifluoromethyl or phenyl.

Preferably, R⁶ is selected from the group consisting of methyl, ethyl,propyl, isopropyl, butyl, isobutyl, allyl, cyclopentyl, cyclohexyl,phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-methylphenyl, 4-methoxyphenyl, 4-carboxyphenyl, 4-hydroxyphenyl,4-nitrophenyl, 4-aminophenyl, 4-dimethylamino-phenyl,3,4-dichlorophenyl, 2,6-dichloro-phenyl 2-trifluoromethyl-phenyl,2,2,2-trifluoroethyl, benzyl, 2-thienyl-methyl, 2-furyl-methyl,2-pyridyl-methyl, 4-biphenyl, 2-pyridyl, 3-pyridyl and5-chloro-6-benzothienyl.

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of hydrogen, halogen, lower alkyl, lower alkenyl, loweralkynyl and cyano; wherein the lower alkyl, the lower alkenyl or thelower alkynyl is optionally substituted on the terminal carbon atom with—Si(lower alkyl)₃. In another embodiment of the present invention R⁴ isselected from the group consisting of hydrogen, halogen, lower alkyl,lower alkenyl, lower alkynyl, cyano and —CC—Si(CH₃)₃. Preferably, R⁴ isselected from the group consisting of hydrogen, chloro, iodo, bromo,methyl, ethyl, —CH═CH₂, —CCH, cyano and —CC—Si(CH₃)₃.

In an embodiment of the present invention R⁵ is selected from the groupconsisting of halogen, lower alkyl, halogen substituted lower alkyl,lower alkoxy, halogen substituted lower alkoxy, cyano, nitro, amino,(lower alkyl)amino, di(lower alkyl)amino, —C(O)-(lower alkyl),—C(O)-(lower alkoxy), —NH—C(O)-(lower alkyl), —NH—C(O)-(trifluoromethyl)and phenyl; wherein the phenyl is optionally substituted with one ormore, preferably, one to two substituents independently selected fromhalogen, hydroxy, carboxy, lower alkyl, trifluoromethyl, lower alkoxy,trifluoromethoxy, cyano, nitro, amino, lower alkylamino or di(loweralkyl)amino.

In another embodiment of the present invention R⁵ is selected from thegroup consisting of halogen, cyano, nitro, amino, lower alkylamino,di(lower alkyl)amino, carboxy, lower-alkyl-carbonyl, loweralkoxy-carbonyl, halogenated lower alkyl, preferably fluorinated loweralkyl, —NHC(O)—CF₃, phenyl and phenyl substituted with a halogen.Preferably, R⁵ is selected from the group consisting of chloro, fluoro,bromo, cyano, nitro, amino, trifluoromethyl, —NHC(O)—CF₃,methoxy-carbonyl and chloro-phenyl.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of halogen lower alkyl, lower alkoxy, trifluoromethyl,cyano, nitro, amino, —NH—C(O)—CF₃, —C(O)-lower alkoxy and phenylsubstituted with halogen. Preferably, R⁵ is selected from the groupconsisting of chloro, bromo, fluoro, iodo, methyl, trifluoromethyl,methoxy, cyano, nitro, amino, —NH—C(O)—CF₃, methoxy-carbonyl- and3-chlorophenyl.

In an embodiment of the present invention, R⁷ is selected from the groupconsisting of hydrogen, lower alkyl and —Si(lower alkyl)₃. In anotherembodiment of the present invention R⁷ is selected from the groupconsisting of hydrogen, lower alkyl and Si(methyl)₃. Preferably, R⁷ isselected from the group consisting of hydrogen, methyl andtrimethyl-silyl.

In an embodiment of the present invention R² is other than methyl and R³is other than methyl. Preferably, R² is other than lower alkyl and R³ isother than lower alkyl.

In an embodiment of the present invention X is O. In another embodimentof the present invention X is NR¹ and R¹ is selected from the groupconsisting of hydrogen, (lower alkyl)-sulfonyl (preferably,methyl-sulfonyl), phenylsulfonyl, toylysulfonyl (preferablyp-tolylsulfonyl), lower alkyl (preferably, methyl or ethyl),—CH₂-(fluorinated lower alkyl) (preferably, 2,2,2-trifluoroethyl),cyano-(lower alkyl) (preferably, cyano-methyl), (lower alkyl)-O-(loweralkyl) (preferably, methoxy-methyl) and (lower alkyl)-S-(lower alkyl)(preferably, methyl-thio-methyl).

In another embodiment of the present invention X is O. In anotherembodiment of the present invention X is NR¹ and R¹ is selected from thegroup consisting of hydrogen, (lower alkyl)-sulfonyl (preferably,methyl-sulfonyl), lower alkyl (preferably, methyl or ethyl),—CH₂-(fluorinated lower alkyl) (preferably, 2,2,2-trifluoroethyl),cyano-(lower alkyl) (preferably, cyano-methyl), (lower alkyl)-O-(loweralkyl) (preferably, methoxy-methyl) and (lower alkyl)-S-(lower alkyl)(preferably, methyl-thio-methyl).

In an embodiment of the present invention R⁷ is hydrogen or lower alkyl(preferably methyl). In another embodiment of the present invention band c are each 0.

In an embodiment of the present invention R⁴ is selected from the groupconsisting of hydrogen, halogen (preferably, chloro, bromo or iodo),cyano, lower alkyl (preferably, methyl or ethyl), lower alkenyl(preferably, —CH═CH₂), lower alkynyl (preferably, —CCH) and—CC—Si(CH₃)₃. In another embodiment of the present invention R⁴ isselected from the group consisting of hydrogen and lower alkyl,preferably, R⁴ is hydrogen or methyl.

In an embodiment of the present invention a is an integer from 0 to 3,preferably 1 to 3 and R⁵ is selected from the group consisting ofhalogen (preferably, chloro, bromo or fluoro), nitro, amino, cyano,(lower alkoxy)-carbonyl (preferably, methoxy-carbonyl), trifluoromethyl,—NHC(O)—CF₃ and halogen substituted phenyl (preferably, chlorophenyl).

In an embodiment of the present invention R² is selected from the groupconsisting of hydrogen, lower alkyl, trifluoromethyl and—(CH₂)—S(O)₀₋₂—R⁵, wherein R⁶ is selected from lower alkyl (preferably,methyl or ethyl). Preferably, R² is selected from the group consistingof hydrogen, methyl, ethyl, trifluoromethyl and —CH₂—S-ethyl. In anotherembodiment of the present invention R² is selected from the groupconsisting of hydrogen and lower alkyl. Preferably, R² is selected fromthe group consisting of hydrogen and methyl. More preferably, R² ismethyl. In another embodiment, R² is selected from the group consistingof hydrogen and trifluoromethyl.

In an embodiment of the present invention R³ is selected from the groupconsisting of lower alkyl, halogen substituted lower alkyl,—(CH₂)₀₋₂—Z—R⁶; wherein Z is selected from —S—, —SO—, —SO₂— and—O—C(O)—; and wherein R⁶ is selected from the group consisting of loweralkyl, lower alkenyl, halogen substituted lower alkyl, cycloalkyl, aryl,aralkyl, heteroaryl and -(lower alkyl)-heteroaryl; wherein the aryl orheteroaryl is optionally substituted with one to two substituentsindependently selected from halogen, hydroxy, carboxy, nitro, amino,(lower alkyl)amino, di(lower alkyl)amino, lower alkyl, lower alkoxy,trifluoromethyl or phenyl.

In another embodiment of the present invention R³ is selected from thegroup consisting of lower alkyl (preferably, methyl), halogensubstituted lower alkyl (preferably, chloromethyl or trifluoromethyl),—(CH₂)₀₋₂—S(O)₀₋₂—R⁶ and —(CH₂)—OC(O)—R⁶; wherein R⁶ is selected fromthe group consisting of lower alkyl (preferably, methyl, ethyl, propyl,isopropyl or butyl), halogen substituted alkyl (preferably,2,2,2-trifluoroethyl), lower alkenyl, lower alkynyl, phenyl (optionallysubstituted with one to two substituents independently selected fromhalogen, hydroxy, carboxy, trifluoromethyl, nitro, amino, (loweralkyl)amino, di(lower alkyl)amino, lower alkyl, lower alkoxy, phenyl,heteroaryl), aralkyl (preferably, benzyl), cycloalkyl (preferably,cyclopentyl or cyclohexyl) and heteroaryl (preferably, thienyl, furyl orpyridyl) (wherein the heteroaryl is optionally substituted with asubstitutent selected from lower alkyl).

In an embodiment, R³ is selected from the group consisting of methyl,chloromethyl, trifluoromethyl, —CH₂—O-(3-nitrophenyl),—CH₂—O-(4-cyanophenyl), —CH₂—O-(3-trifluoromethyl-4-cyano-phenyl),—S-methyl, —S-isopropyl, —S-cyclohexyl, S-phenyl, —S-(4-chlorophenyl),—S-(4-fluorophenyl), —S-(3,4-dichlorophenyl), —S-(4-aminophenyl),—SO₂-(4-chlorophenyl), —SO₂-(3,4-dichlorophenyl), —CH₂—S-methyl,—CH₂—S-ethyl, —CH₂—S-butyl, —CH₂—S-propyl, —CH₂—S-isopropyl,—CH₂—S-isobutyl, —CH₂—S-allyl, —CH₂—S-phenyl, —CH₂—S-(2-chlorophenyl),—CH₂—S-(4-chlorophenyl), —CH₂—S-(4-fluorophenyl),—CH₂—S-(4-methoxyphenyl), —CH₂—S-(4-carboxyphenyl),—CH₂—S-(4-hydroxyphenyl), —CH₂—S-(4-nitrophenyl),—CH₂—S-(4-aminophenyl), —CH₂—S-(4-dimethylamino-phenyl),—CH₂—S-(3,4-dichlorophenyl), —CH₂—S-(2,2,2-trifluoroethyl),—CH₂—S-benzyl, —CH₂—S-cyclopentyl, —CH₂—S-cyclohexyl,—CH₂—S-(2-thienyl-methyl), —CH₂—S-(2-furyl-methyl),—CH₂—S-(2-pyridyl-methyl), —CH₂—SO-ethyl, —CH₂—SO-phenyl,—CH₂—SO-(3,4-dichlorophenyl), —CH₂—SO-(2,2,2-trifluoroethyl),—CH₂—SO-benzyl, —CH₂—SO₂-methyl, —CH₂—SO₂-ethyl, —CH₂—SO₂-propyl,—CH₂—SO₂-(4-fluorophenyl), —CH₂—SO₂-(4-hydroxyphenyl),—CH₂—SO₂-(4-aminophenyl), —CH₂—SO₂-(4-dimethylamino-phenyl),—CH₂—SO₂-(4-methoxyphenyl), —CH₂—SO₂-(2,2,2-trifluoroethyl),—CH₂—SO₂-benzyl, —CH₂CH₂—S-methyl, —CH₂CH₂—SO-methyl,—CH₂CH₂—SO₂-methyl, —CH₂—O—C(O)-(2-chlorophenyl),—CH₂—O—C(O)-(3-chlorophenyl), —CH₂—O—C(O)-(4-chlorophenyl),—CH₂—O—C(O)-(4-fluorophenyl), —CH₂—O—C(O)-(4-nitrophenyl),—CH₂—O—C(O)-(4-methyl-phenyl), —CH₂—O—C(O)-(4-methoxy-phenyl),—CH₂—O—C(O)-(2-trifluoro-methyl-phenyl), —CH₂—O—C(O)-(4-t-butyl-phenyl),—CH₂—O—C(O)-phenyl, —CH₂—O—C(O)-(3,4-dichloro-phenyl),—CH₂—O—C(O)-(2,6-dichloro-phenyl),—CH₂—O—C(O)-(4-dimethyl-amino-phenyl), —CH₂—O—C(O)-(4-biphenyl),—CH₂—O—C(O)-(2-pyridyl), —CH₂—O—C(O)-(3-pyridyl) and—CH₂—O—C(O)-(5-chloro-6-benzothienyl).

Preferably, R³ is selected from the group consisting of methyl,chloromethyl, trifluoromethyl, —S-methyl, —S-isopropyl, —S-cyclohexyl,S-phenyl, —S-(4-chlorophenyl), —S-(4-fluorophenyl),—S-(3,4-dichlorophenyl), —S-(4-aminophenyl), —SO₂-(4-chlorophenyl),—SO₂-(3,4-dichlorophenyl), —CH₂—S-methyl, —CH₂—S-ethyl, —CH₂—S-butyl,—CH₂—S-propyl, —CH₂—S-isopropyl, —CH₂—S-isobutyl, —CH₂—S-allyl,—CH₂—S-phenyl, —CH₂—S-(2-chlorophenyl), —CH₂—S-(4-chlorophenyl),—CH₂—S-(4-fluorophenyl), —CH₂—S-(4-methoxyphenyl),—CH₂—S-(4-carboxyphenyl), —CH₂—S-(4-hydroxyphenyl),—CH₂—S-(4-nitrophenyl), —CH₂—S-(4-aminophenyl),—CH₂—S-(4-dimethylamino-phenyl), —CH₂—S-(3,4-dichlorophenyl),—CH₂—S-(2,2,2-trifluoroethyl), —CH₂—S-benzyl, —CH₂—S-cyclopentyl,—CH₂—S-cyclohexyl, —CH₂—S-(2-thienyl-methyl), —CH₂—S-(2-furyl-methyl),—CH₂—S-(2-pyridyl-methyl), —CH₂—SO-ethyl, —CH₂—SO-phenyl,—CH₂—SO-(3,4-dichlorophenyl), —CH₂—SO-(2,2,2-trifluoroethyl),—CH₂—SO-benzyl, —CH₂—SO₂-methyl, —CH₂—SO₂-ethyl, —CH₂—SO₂-propyl,—CH₂—SO₂-(4-fluorophenyl), —CH₂—SO₂-(4-hydroxyphenyl),—CH₂—SO₂-(4-aminophenyl), —CH₂—SO₂-(4-dimethylamino-phenyl),—CH₂—SO₂-(4-methoxyphenyl), —CH₂—SO₂-(2,2,2-trifluoroethyl),—CH₂—SO₂-benzyl, —CH₂CH₂—S-methyl, —CH₂CH₂—SO-methyl,—CH₂CH₂—SO₂-methyl, —CH₂—O—C(O)-(2-chlorophenyl),—CH₂—O—C(O)-(3-chlorophenyl), —CH₂—O—C(O)-(4-chlorophenyl),—CH₂—O—C(O)-(4-fluorophenyl), —CH₂—O—C(O)-(4-nitrophenyl),—CH₂—O—C(O)-(4-methyl-phenyl), —CH₂—O—C(O)-(4-methoxy-phenyl),—CH₂—O—C(O)-(2-trifluoro-methyl-phenyl), —CH₂—O—C(O)-(4-t-butyl-phenyl),—CH₂—O—C(O)-phenyl, —CH₂—O—C(O)-(3,4-dichloro-phenyl),—CH₂—O—C(O)-(2,6-dichloro-phenyl),—CH₂—O—C(O)-(4-dimethyl-amino-phenyl), —CH₂—O—C(O)-(4-biphenyl),—CH₂—O—C(O)-(2-pyridyl), —CH₂—O—C(O)-(3-pyridyl) and—CH₂—O—C(O)-(5-chloro-6-benzothienyl).

In an embodiment of the present invention a is 2 and R⁵ is selected fromthe group consisting of halogen (preferably, chloro), nitro, cyano andtrifluoromethyl. In another embodiment of the present invention b and care each 0. In another embodiment of the present invention R⁴ ishydrogen. In another embodiment of the present invention R⁷ is hydrogen.In another embodiment of the present invention R¹ is selected from thegroup consisting of H and lower alkyl-sulfonyl (preferably,methyl-sulfonyl).

In an embodiment of the present invention

is a five to six membered, saturated or partially unsaturated ringstructure containing one to two heteroatoms selected from O, S or N;wherein the five to six membered, saturated or partially unsaturatedring is optionally substituted with a substituent selected from aralkyl(wherein the aralkyl is optionally substituted with one to twosubstituents selected independently from the group consisting ofhalogen, lower alkyl, lower alkoxy, lower alkylsulfonyl andtrifluoromethyl), aryl (wherein the aryl is optionally substituted withone to two substituents selected independently from the group consistingof halogen, lower alkyl, lower alkoxy, lower alkylsulfonyl andtrifluoromethyl) and aralkyloxy-carbonyl.

Preferably,

is selected from the group consisting of tetrahydro-thien-3-yl,(S)-tetrahydro-thien-3-yl, (R)-tetrahydro-thien-3-yl,tetrahydro-thiopyran-4-yl, 4-(1-benzyloxy-carbonyl-piperidinyl),4-(1-benzyl-piperidinyl), 4-piperidinyl,4-(1-(4-chlorophenyl)-carbonyl-piperidinyl),4-(1-(4-trifluoromethyl-benzyl)-piperidinyl),4-(1-(4-methyl-benzyl)-piperidinyl),4-(1-(4-fluoro-benzyl)-piperidinyl),4-(1-(3-methoxy-benzyl)-piperidinyl),4-(1-(4-chloro-benzyl)-piperidinyl),4-(1-(4-t-butyl-benzyl)-piperidinyl),4-(1-(4-methylsulfonyl-benzyl)-piperidinyl),4-(1-(4-methoxy-benzyl)-piperidinyl) and4-(1-(3,4-dichloro-benzyl)-piperidinyl).

In an embodiment of the present invention

is pyridyl. In another embodiment of the present invention a R¹ ishydrogen. In another embodiment of the present invention a is 1 and R⁵is selected from cyano or trifluoromethyl. In another embodiment of thepresent invention b and c are each 0. In another embodiment of thepresent invention R² is lower alkyl (preferably, methyl).

In an embodiment of the present invention R³ is selected from the groupconsisting of halogenated lower alkyl and -(lower alkyl)-S(O)₀₋₂—R⁶.Preferably, R³ is selected from the group consisting of chloromethyl and—CH₂—S—R⁶. Preferably, R³ is selected from the group consisting ofchloromethyl, —CH₂—S-ethyl, —CH₂—S-phenyl, —CH₂—S-(4-chlorophenyl),—CH₂—S-(4-fluorophenyl) and —CH₂—S-cyclohexyl.

In an embodiment of the present invention R⁶ is selected from the groupconsisting of lower alkyl, cycloalkyl and aryl (wherein the aryl isoptionally substituted with a halogen). Preferably, R⁶ is selected fromthe group consisting of ethyl, cyclohexyl, phenyl, 4-chlorophenyl and4-fluorophenyl.)

In an embodiment of the present invention are compounds of formula (I)wherein R¹ is selected from hydrogen or methyl-sulfonyl, R⁴ is selectedfrom hydrogen, halogen, cyano, —CH═CH₂, —CCH or —CC—Si(CH₃)₃(preferably, R⁴ is selected from hydrogen, halogen or cyano, morepreferably, R⁴ is hydrogen or halogen), R⁷ is hydrogen, R² and R³ areeach methyl, b is 0, c is 0, a is an integer from 1 to 2, each R⁵ isindependently selected from halogen (preferably, bromo or chloro),cyano, nitro and trifluoromethyl and the R⁵ groups are bound at the 5and 6 positions.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e.

a, b, c, X, Y, R², R³, R⁴, R⁵ and R⁷) are independently selected to beany individual substituent or any subset of substituents selected fromthe complete list as defined herein.

In an embodiment of the present invention, the stereoconfiguration atthe carbon atom bound to R², R³ and —(CH₂)_(c)—OR⁷ (i.e. the starred (*)carbon atom in the Tables below) is in the (+) configuration. In anotherembodiment of the present invention, the stereoconfiguration at thecarbon atom bound to R², R³ and —(CH₂)_(c)—OR⁷ (i.e. the starred (*)carbon atom in the Tables below) is in the (−) configuration.

Representative compounds of the present invention are as listed inTables 1, 2, 3, 4 and 5 below. In Tables 2, 3, 4 and 5 the column headedwith the “*” symbol denotes the stereo-configuration of the tertiarycarbon. The “+” and “−” configurations are based on experimentaldetermination. (The absolute configuration may or may not have beendetermined.) A notation of “±” indicates a mixture of configurations. Anotation of “n/a” indicates that no stereo-center was present. Unlessotherwise noted, for compounds listed below wherein R² contains an —SO—group, said chiral center was present as a mixture of configurations.

TABLE 1 Compounds of Formula (II)

ID No R¹

(R⁵)_(a) 14 H tetrahydro-thien-3-yl 5-chloro, 6-CF₃ 15 Htetrahydro-thien-3-yl 5-cyano, 6-CF₃ 16 methyl-sulfonyltetrahydro-thiopyran-4-yl 5-nitro, 6-CF₃ 17 H tetrahydro-thiopyran-4-yl5-nitro, 6-CF₃ 18 H tetrahydro-thien-3-yl 5-nitro, 6-CF₃ 19methyl-sulfonyl 4-(1-benzyloxy-carbonyl- 5-chloro, 6-CF₃ piperidinyl) 20H 4-(1-benzyloxy-carbonyl- 5-chloro, 6-CF₃ piperidinyl) 21methyl-sulfonyl 4-(1-benzyl-piperidinyl) 5-chloro, 6-CF₃ 22 H4-(1-benzyl-piperidinyl) 5-chloro, 6-CF₃ 23 methyl-sulfonyl4-piperidinyl 5-chloro, 6-CF₃ 24 methyl-sulfonyl 4-(1-(4-chlorophenyl)-5-chloro, 6-CF₃ carbonyl-piperidinyl) 25 H 4-(1-(4-chlorophenyl)-5-chloro, 6-CF₃ carbonyl-piperidinyl) 26 H 4-(1-(4-trifluoromethyl-5-nitro, 6-CF₃ benzyl)-piperidinyl) 27 H 4-(1-(4-methyl-benzyl)-5-nitro, 6-CF₃ piperidinyl) 28 H 4-(1-(4-fluoro-benzyl)- 5-chloro, 6-CF₃piperidinyl) 29 H 4-(1-(3-methoxy-benzyl)- 5-chloro, 6-CF₃ piperidinyl)30 H 4-(1-(4-methyl-benzyl)- 5-chloro, 6-CF₃ piperidinyl) 31 H4-(1-(4-chloro-benzyl)- 5-chloro, 6-CF₃ piperidinyl) 32 H4-(1-(4-t-butyl-benzyl)- 5-chloro, 6-CF₃ piperidinyl) 33 H4-(1-(4-trifluoromethyl- 5-chloro, 6-CF₃ benzyl)-piperidinyl) 34 H4-(1-(4-methylsulfonyl- 5-chloro, 6-CF₃ benzyl)-piperidinyl) 35 H4-(1-(4-methoxy-benzyl)- 5-chloro, 6-CF₃ piperidinyl) 36 H4-(1-(3,4-dichloro-benzyl)- 5-chloro, 6-CF₃ piperidinyl) 37 H4-(1-(4-fluoro-benzyl)- 5-nitro, 6-CF₃ piperidinyl) 38 H4-(1-(3-methoxy-benzyl)- 5-nitro, 6-CF₃ piperidinyl) 39 H4-(1-(3-methoxy-benzyl)- 5-nitro, 6-CF₃ piperidinyl) 40 H4-(1-(4-chloro-benzyl)- 5-nitro, 6-CF₃ piperidinyl) 41 H4-(1-(4-chloro-benzyl)- 5-nitro, 6-CF₃ piperidinyl) 42 H4-(1-(4-methyl-benzyl)- 5-nitro, 6-CF₃ piperidinyl 43 H4-(1-(3,4-dichloro-benzyl)- 5-nitro, 6-CF₃ piperidinyl)

TABLE 2 Compounds of Formula (I)

ID No * R¹ R² R³ R⁴ (R⁵)_(a) 13 na H —CH₂—S— —CH₂—S-ethyl H 5-nitro, 6-ethyl CF₃ 47 ± H methyl —CH₂CH₂—S— H 5-nitro, 6- methyl CF₃ 48 ± methyl-methyl —CH₂CH₂—S— H 5-nitro, 6- sulfonyl methyl CF₃ 49 ± H methyl—CH₂CH₂—SO₂— H 5-nitro, 6- methyl CF₃ 50 ± H methyl —CH₂CH₂—SO— H5-nitro, 6- methyl CF₃ 51 ± H methyl —CH₂CH₂—S— H 5-chloro, methyl 6-CF₃52 ± H methyl —CH₂—O—C(O)— H 5-nitro, 6- (2,6-dichloro- CF₃ phenyl) 53 ±H methyl —CH₂—O—C(O)— H 5-chloro (4-chloro- phenyl) 54 ± H methyl—CH₂—O—C(O)— H 5-nitro, 6- (2-chloro- CF₃ phenyl) 55 ± H methyl—CH₂—O—C(O)— H 5-nitro, 6- (4-chloro- CF₃ phenyl) 56 ± H methyl—CH₂—O—C(O)— H 5-nitro, 6- (3,4-dichloro- CF₃ phenyl) 57 ± H methyl—CH₂—O—C(O)— H 5-nitro, 6- (2-trifluoro- CF₃ methyl-phenyl) 58 ± Hmethyl —CH₂—O—C(O)— H 5-nitro, 6- (3- CF₃ chlorophenyl) 59 ± H methyl—CH₂—O—C(O)— H 5-amino, (2-trifluoro- 6-CF₃ methyl-phenyl) 60 ± H methyl—CH₂—O—C(O)— H 5-CF₃— (2-trifluoro- C(O)NH—, methyl-phenyl) 6-CF₃ 61 ± Hmethyl —CH₂—C(O)— H 5-chloro, phenyl 6-CF₃ 62 ± H methyl —CH₂—O—C(O)— H5-chloro, (4-chloro- 6-CF₃ phenyl) 63 ± H methyl —CH₂—O—C(O)— H 5-nitro,6- (4-nitrophenyl) CF₃ 64 ± H methyl —CH₂—O—C(O)— H 5-nitro, 6- phenylCF₃ 65 ± H methyl —CH₂—O—C(O)— H 5-nitro, 6- (4-methoxy- CF₃ phenyl) 66± H methyl —CH₂—O—C9O)— H 5-nitro, 6- (4-biphenyl) CF₃ 67 ± H methyl—CH₂—O—C(O)— H 5-nitro, 6- (4-dimethyl- CF₃ amino-phenyl) 68 ± H methyl—CH₂O—C(O)— H 5-nitro, 6- (2-pyridyl) CF₃ 69 ± H methyl —CH₂—O—C(O)— H5-nitro, 6- (4-methyl- CF₃ phenyl) 70 ± H methyl —CH₂—O—C(O)— H 5-nitro,6- (5-chloro-6- CF₃ benzothienyl) 75 ± H methyl —CH₂—O—C(O)— H 5-cyano,6- phenyl CF₃ 76 ± H methyl —CH₂—O—C(O)— H 5-cyano, 6- (4-chloro- CF₃phenyl) 77 ± H methyl —CH₂—O—C(O)— H 5-cyano, 6- (4-fluorophenyl) CF₃ 78± H methyl —CH₂—O—C(O)— H 5-cyano, 6- (3,4-dichloro- CF₃ phenyl) 79 ± Hmethyl —CH₂—O—C(O)— H 5-cyano, 6- (3-pyridyl) CF₃ 80 ± H methyl—CH₂—O—C(O)— H 5-nitro, 6- (4-t-butyl- CF₃ phenyl) 81 ± methyl- methyl—CH₂—S-phenyl H 5-methoxy- sulfonyl carbonyl 82 ± H methyl —CH₂—S-(4- H5-chloro, chlorophenyl) 6-CF₃ 83 ± H methyl —CH₂—S-(4- H 5-chloro,fluorophenyl) 6-CF₃ 84 ± H methyl —CH₂—S-(2- H 5-chloro, chlorophenyl)6-CF₃ 85 ± H methyl —CH₂—SO₂-(4- H 5-chloro, fluorophenyl) 6-CF₃ 86 ±methyl- methyl —CH₂—S-(3,4- H 5-chloro, sulfonyl dichlorophenyl) 6-CF₃87 ± H methyl —CH₂—S-(3,4- H 5-nitro, 6- dichlorophenyl) CF₃ 88 ±methyl- methyl —CH₂—S-(4- H a = 0 sulfonyl chlorophenyl) 89 ± H methyl—CH₂—S-(4- H a = 0 chlorophenyl) 90 ± methyl- methyl —CH₂—S-phenyl H a =0 sulfonyl 91 ± methyl- methyl —CH₂—S-(3,4- H 5-nitro, 6- sulfonyldichlorophenyl) CF₃ 92 ± H methyl —CH₂—S— H 5-cyano, 6- cyclohexyl CF₃93 ± methyl- methyl —CH₂—S— H 5-methoxy- sulfonyl cyclohexyl carbonyl 94± H methyl —CH₂—S— H 5-methoxy- cyclohexyl carbonyl 95 ± H methyl—CH₂—S-phenyl H 5-cyano, 6- CF₃ 96 ± H methyl —CH₂—S-(4- H 5-cyano, 6-chlorophenyl) CF₃ 97 ± H methyl —CH₂—S-(4- H 5-methoxy- chlorophenyl)carbonyl 98 ± methyl- methyl —CH₂—S-(4- H 5-methoxy- sulfonylfluorophenyl) carbonyl 99 ± methyl- methyl —CH₂—S-(4- H 5-chlorosulfonyl fluorophenyl) 100 ± H methyl —CH₂—S-(4- H 5-chlorofluorophenyl) 101 ± methyl- methyl —CH₂—S-(4- H 5-chloro sulfonylchlorophenyl) 102 ± H methyl —CH₂—S-(4- H 5-chloro chlorophenyl) 103 ± Hmethyl —CH₂—S-(4- H 5-nitro, 6- nitrophenyl) CF₃ 104 ± H methyl—CH₂—S-(4- 5-chloro, aminophenyl) 6-CF₃ 105 ± H methyl —CH₂—S-(3,4- H5-chloro, dichlorophenyl) 6-CF₃ 106 ± H methyl —CH₂—S-phenyl H 5-chloro,6-CF₃ 107 ± methyl- methyl —CH₂—S-(4- H a = 0 sulfonyl fluorophenyl) 108± H methyl —CH₂—S-(4- H a = 0 fluorophenyl) 109 ± H methyl —CH₂—S-(4- H5-cyano, 6- fluorophenyl) CF₃ 110 ± H methyl —CH₂—SO₂-(4- H 5-cyano, 6-fluorophenyl) CF₃ 112 ± H methyl —CH₂—SO— H 5-chloro, phenyl 6-CF₃ 113(b) H methyl —CH₂—SO-(4- H 5-chloro, fluorophenyl) 6-CF₃ 114 (b) Hmethyl —CH₂—SO-(4- H 5-chloro, fluorophenyl) 6-CF₃ 115 ± H methyl—CH₂—SO— H 5-chloro, phenyl 6-CF₃ 116 (b) H methyl —CH₂—SO-(3,4- H5-chloro, dichlorophenyl) 6-CF₃ 117 (b) H methyl —CH₂—SO-(3,4- H5-chloro, dichlorophenyl) 6-CF₃ 118 ± H methyl —CH₂—SO₂-(4- H 5-chloro,aminophenyl) 6-CF₃ 119 ± methyl- methyl —CH₂—S-(4- H 5-chloro, sulfonylhydroxyphenyl) 6-CF₃ 120 ± H methyl —CH₂—S-(4- H 5-chloro,hydroxyphenyl) 6-CF₃ 121 ± H methyl —CH₂—SO₂-(4- H 5-chloro,hydroxyphenyl) 6-CF₃ 122 ± H methyl —CH₂—S-(4- H 5-chloro, nitrophenyl)6-CF₃ 123 ± H methyl —CH₂—S-(2- H 5-chloro, aminophenyl) 6-CF₃ 124 ± Hmethyl —CH₂—S-(4- H 5-chloro, dimethylamino- 6-CF₃ phenyl) 125 ± methyl-methyl —CH₂—S-(4- H 5-chloro, sulfonyl aminophenyl) 6-CF₃ 126 ± H methyl—CH₂—SO₂-(4- H 5-chloro, dimethylamino- 6-CF₃ phenyl) 127 ± H methyl—CH₂—S-(2- H 5-chloro, dimethylamino- 6-CF₃ phenyl) 128 ± methyl- methyl—CH₂—SO₂-(4- H 5-chloro, sulfonyl methoxyphenyl) 6-CF₃ 129 ± H methyl—CH₂—SO₂-(4- H 5-chloro, methoxyphenyl) 6-CF₃ 130 ± methyl- methyl—CH₂—S-(4- H 5-chloro, sulfonyl methoxyphenyl) 6-CF₃ 131 ± H methyl—CH₂—S-(4- H 5-chloro, methoxyphenyl) 6-CF₃ 132 ± methyl- methyl—CH₂—S-(4- H 5-chloro, sulfonyl carboxyphenyl) 6-CF₃ 133 ± H methyl—CH₂—S-(4- H 5-chloro, carboxyphenyl) 6-CF₃ 134 ± methyl- methyl—CH₂—S-methyl H 5-chloro, sulfonyl 6-CF₃ 135 ± H methyl —CH₂—S-methyl H5-chloro, 6-CF₃ 136 ± H methyl —CH₂—S-methyl H 5-cyano, 6- CF₃ 137 ±methyl- methyl —CH₂—SO₂— H 5-chloro, sulfonyl methyl 6-CF₃ 138 ± Hmethyl —CH₂—SO₂— H 5-chloro, methyl 6-CF₃ 139 ± H methyl —CH₂—S-methyl H5-nitro, 6- CF₃ 140 ± H methyl —CH₂—SO₂— H 5-nitro, 6- methyl CF₃ 141 ±methyl- methyl —CH₂—S-ethyl H 5-nitro, 6- sulfonyl CF₃ 142 ± H methyl—CH₂—S-ethyl H 5-nitro, 6- CF₃ 143 ± H methyl —CH₂—SO₂-ethyl H 5-nitro,6- CF₃ 144 + H methyl —CH₂—S-methyl H 5-nitro, 6- CF₃ 145 − H methyl—CH₂—S-methyl H 5-nitro, 6- CF₃ 146 ± methyl- methyl —CH₂—S-ethyl H5-chloro, sulfonyl 6-CF₃ 147 + H methyl —CH₂—SO₂— H 5-nitro, 6- methylCF₃ 148 − H methyl —CH₂—SO₂— H 5-nitro, 6- methyl CF₃ 149 + H methyl—CH₂—S-ethyl H 5-nitro, 6- CF₃ 150 − H methyl —CH₂—S-ethyl H 5-nitro, 6-CF₃ 151 −^((a)) H methyl —CH₂—SO₂-ethyl H 5-nitro, 6- CF₃ 152 ± H methyl—CH₂—S-ethyl H 5-chloro, 6-CF₃ 153 ± H methyl —CH₂—S-ethyl H 5-nitro, 6-CF₃ 154 ± methyl- methyl —CH₂—S-ethyl H 5-chloro sulfonyl 155 −^((a)) Hmethyl —CH₂—SO-ethyl H 5-nitro, 6- CF₃ 156 +^((a)) H methyl—CH₂—SO₂-ethyl H 5-nitro, 6- CF₃ 157 ± methyl- H —CH₂—SO₂-ethyl H5-nitro, 6- sulfonyl CF₃ 158 ± H H —CH₂—S-ethyl H 5-nitro, 6- CF₃ 159 ±H methyl —CH₂—S-ethyl H 5-fluoro, 6- CF₃ 160 ± H methyl —CH₂—S-benzyl H5-nitro, 6- CF₃ 161 ± H methyl —CH₂—SO-benzyl H 5-nitro, 6- CF₃ 162 ± Hmethyl —CH₂—SO₂— H 5-nitro, 6- benzyl CF₃ 163 ± H methyl —CH₂—S— H5-nitro, 6- isopropyl CF₃ 164 ± H methyl —CH₂—S— H 5-nitro, 6- isopropylCF₃ 165 ± methyl methyl —CH₂—S-ethyl H 5-nitro, 6- CF₃ 166 ± H methyl—CH₂—S-ethyl H 5-amino, 6-CF₃ 168 ± H methyl —CH₂—S-n-propyl H 5-nitro,6- CF₃ 169 ± H ethyl —CH₂—S-ethyl H 5-nitro, 6- CF₃ 170 ± H methyl—CH₂—S-isobutyl H 5-nitro, 6- CF₃ 171 ± H methyl —CH₂—S-(2,2,2- H5-nitro, 6- CF₃ 172 ± methyl- methyl —CH₂—S-(2,2,2- H 5-nitro, 6-sulfonyl trifluoroethyl) CF₃ 173 ± H methyl —CH₂—S— H 5-nitro, 6-cyclopentyl CF₃ 174 ± methyl- methyl —CH₂—S— H 5-nitro, 6- sulfonylcyclopentyl CF₃ 175 ± H methyl —CH₂—SO₂-ethyl H 5-nitro, 6- CF₃ 176 ± Hethyl —CH₂—SO₂-ethyl H 5-nitro, 6- CF₃ 177 ± H methyl —CH₂—SO₂-n- H5-nitro, 6- propyl CF₃ 178 ± H methyl —CH₂—S-ethyl H a = 0 180 ± H H—CH₂—SO-ethyl H 5-nitro, 6- CF₃ 181 ± H ethyl —CH₂—S-ethyl H 5-chloro,6-CF₃ 182 ± methyl- ethyl —CH₂—S-(2,2,2- H 5-nitro, 6- sulfonyltrifluoroethyl) CF₃ 183 ± methyl- methyl —CH₂—S-(2- H 5-nitro, 6-sulfonyl thienyl-methyl) CF₃ 184 ± methyl- methyl —CH₂—S-allyl H5-nitro, 6- sulfonyl CF₃ 185 ± H ethyl —CH₂—S-(2,2,2- H 5-nitro, 6-trifluoroethyl) CF₃ 186 ± methyl- ethyl —CH₂—S-(2,2,2- H 5-chloro,sulfonyl trifluoroethyl) 6-CF₃ 187 ± methyl- methyl —CH₂—S-(2,2,2- H5-chloro, sulfonyl trifluoroethyl) 6-CF₃ 188 ± methyl- methyl—CH₂—S-(2,2,2- H 5-fluoro, 6- sulfonyl trifluoroethyl) CF₃ 189 ± Hmethyl —CH₂—S-(2,2,2- H 5-fluoro, 6- trifluoroethyl) CF₃ 190 ± H methyl—CH₂—S-(2,2,2- H 5-chloro, trifluoroethyl) 6-CF₃ 191 ± H ethyl —CH₂—SO₂—H 5-nitro, 6- (2,2,2- CF₃ trifluoroethyl) 192 ± H ethyl —CH₂—S-(2,2,2- H5-chloro, trifluoroethyl) 6-CF₃ 193 ± methyl- ethyl —CH₂—S-(2,2,2- H5-fluoro, 6- sulfonyl trifluoroethyl) CF₃ 194 ± H ethyl —CH₂—S-(2,2,2- H5-fluoro, 6- trifluoroethyl) CF₃ 195 ± methyl- methyl —CH₂—S-n-butyl H5-nitro, 6- sulfonyl CF₃ 196 ± H methyl —CH₂—S-propyl H 5-chloro, 6-CF₃197 ± H methyl —CH₂—S-(2- H 5-nitro, 6- thienyl-methyl) CF₃ 198 ± Hmethyl —CH₂—S-(2-furyl- H 5-nitor, 6- methyl) CF₃ 199 ± H ethyl—CH₂—SO₂— chloro 5-nitro, 6- (2,2,2- CF₃ trifluoroethyl) 200 ± H methyl—CH₂—S-n-butyl H 5-nitro, 6- CF₃ 201 + H methyl —CH₂—S-(2,2,2- H5-nitro, 6- trifluoroethyl) CF₃ 202 − H methyl —CH₂—S-(2,2,2- H 5-nitro,6- trifluoroethyl) CF₃ 203 ± methyl- methyl —CH₂—S-ethyl H 5-fluoro, 6-sulfonyl chloro 204 ± H methyl —CH₂—S-(2- H 5-nitro, 6- pyridyl-methyl)CF₃ 205 ± H methyl —CH₂—SO-(2,2,2- H 5-nitro, 6- trifluoroethyl) CF₃ 206± H methyl —CH₂—S-ethyl H 5-fluoro, 6- chloro 207 ± H methyl —CH₂—SO₂—chloro 5-CF₃, 6- (2,2,2- nitro trifluoroethyl) 208 ± H methyl —CH₂—SO₂—H 5-nitro, 6- (2,2,2- CF₃ trifluoroethyl) 209 ± H methyl —CH₂—S-ethyl H5-cyano, 6- CF₃ 210 ± H methyl —CH₂—S-(4- H 5-chloro, aminophenyl) 6-CF₃211 ± H methyl —CH₂—S-(2,2,2- H 5-cyano, 6- trifluoroethyl) CF₃ 212 ± Hmethyl —CH₂—S-ethyl H 5-nitro, 7- CF₃ 213 ± H methyl —CH₂—S-(2,2,2- iodo5-nitro, 6- trifluoroethyl) CF₃ 214 ± methyl- methyl —CH₂—S-ethyl H6-CF₃ sulfonyl 215 ± methyl- methyl —CH₂—S-ethyl H 5-cyano, 6- sulfonylCF₃ 216 ± methyl- ethyl —CH₂—S-ethyl H 5-nitro, 6- sulfonyl CF₃ 217 − Hmethyl —CH₂—S-ethyl H 5-cyano, 6- CF₃ 218 + H methyl —CH₂—S-ethyl H5-cyano, 6- CF₃ 219 ± H methyl —CH₂—S-ethyl methyl 5-cyano, 6- CF₃ 220 ±H methyl —CH₂—S-ethyl methyl 5-bromo, 6-CF₃ 221 ± H methyl —CH₂—S-ethylmethyl 5-nitro, 6- CF₃ 222 − H methyl —CH₂—SO₂-ethyl H 5-cyano, 6- CF₃223 ± H ethyl —CH₂—S-ethyl H 5-cyano, 6- CF₃ 224 ± H methyl —CH₂—S-ethylH 5-cyano, 6- chloro 225 − H methyl —CH₂—S-ethyl H 5-cyano, 6- chloro226 ± methyl methyl —CH₂—S-ethyl H 5-cyano, 6- chloro 227 ± H methyl—CH₂—S-ethyl H 5,6- dichloro 228 + H methyl —CH₂—S-ethyl H 5-chloro,6-cyano 229 ± methyl- methyl —CH₂—S-benzyl H 5-nitro, 6- sulfonyl CF₃230 ± H methyl —CH₂—SO-ethyl H 5-CF₃, 6- nitro 231 −^((a)) methyl methyl—CH₂—S-ethyl H 5-nitro, 6- CF₃ 232 −^((a)) methyl methyl —CH₂—SO₂-ethylH 5-nitro, 6- CF₃ 233 − H methyl —CH₂—S-ethyl methyl 5-cyano, 6- CF₃234 + H methyl —CH₂—S-ethyl methyl 5-cyano, 6- CF₃ 236 ± methyl methyl—CH₂—S-ethyl H 5-cyano, 6- CF₃ 237 ± 2,2,2- methyl —CH₂—S-ethyl H5-cyano, 6- trifluoro- CF₃ ethyl 238 ± methyl- methyl —CH₂—S-(2-furyl- H5-nitro, 6- sulfonyl methyl) CF₃ 239 ± methyl- methyl —CH₂—S-propyl H5-chloro, sulfonyl 5-CF₃ 240 ± methyl methyl —CH₂—SO₂-ethyl H 5-cyano,6- CF₃ 241 +^((a)) H methyl —CH₂—S-ethyl iodo 5-nitro, 6- CF₃ 242+^((a)) H methyl —CH₂—S-ethyl cyano 5-nitro, 6- CF₃ 243 ± ethyl methyl—CH₂—S-ethyl H 5-cyano, 6- CF₃ 244 −^((a)) H methyl —CH₂—S-ethyl iodo5-nitro, 6- CF₃ 245 ± H methyl —CH₂—SO-ethyl methyl 5-cyano, 6- CF₃ 246± H methyl —CH₂—SO₂-ethyl methyl 5-cyano, 6- CF₃ 247 − H methyl—CH₂—S-ethyl cyano 5-nitro, 6- CF₃ 248 −^((a)) H methyl —CH₂—SO-ethyl H5-cyano, 6- CF₃ 250 −^((a)) methyl methyl —CH₂—SO₂-ethyl H 5-nitro, 6-CF₃ 251 − H methyl —CH₂—SO₂-ethyl methyl 5-cyano, 6- CF₃ 252 −^((a)) Hmethyl —CH₂—SO-ethyl methyl 5-cyano, 6- CF₃ 254 ± H methyl —S-(3,4- H5-nitro, 6- dichlorophenyl) CF₃ 255 ± H methyl —SO₂-(3,4- H 5-nitro, 6-dichlorophenyl) CF₃ 256 ± H methyl —S-cycloehxyl H 5-nitro, 6- CF₃ 257 ±H methyl —S-cyclohexyl H 5-cyano, 6- CF₃ 258 ± H methyl —S-phenyl H5-nitro, 6- CF₃ 259 ± H methyl —S-(4- H 5-nitro, 6- chlorophenyl) CF₃260 ± H methyl —S-(4- H 5-nitro, 6- fluorophenyl) CF₃ 261 ± H methyl—S-(4- H 5-cyano, 6- chlorophenyl) CF₃ 262 ± H methyl —SO₂-(4- H5-cyano, 6- chlorophenyl) CF₃ 265 ± H methyl —S-(4- H 5-chloro,aminophenyl) 6-CF₃ 266 ± H methyl —S-(4- H 5-nitro, 6- aminophenyl) CF₃267 ± H methyl —S-methyl H 5-nitro, 6- CF₃ 273 na methyl- methyl methylH 5-nitro, 6- sulfonyl CF₃ 274 na H methyl methyl H 5-nitro, 6- CF₃ 275na H methyl methyl chloro 5-nitro, 6- CF₃ 276 na H methyl methyl iodo5-nitro, 6- CF₃ 277 na H methyl methyl bromo 5-nitro, 6- CF₃ 278 na Hmethyl methyl iodo 5-cyano, 6- CF₃ 279 na H methyl methyl iodo 5-chloro,6-CF₃ 280 na H methyl methyl bromo 5-chloro, 6-CF₃ 281 na H methylmethyl —CH═CH₂ 5-nitro, 6- CF₃ 282 na H methyl methyl chloro 5-chloro,6-CF₃ 283 na methyl- methyl methyl H 5-cyano, 6- sulfonyl CF₃ 284 namethyl- methyl methyl H 5-chloro, sulfonyl 6-CF₃ 285 na H methyl methylH 5-chloro, 6-CF₃ 286 na H methyl methyl H 5-cyano, 6- CF₃ 287 na Hmethyl methyl chloro 5-cyano, 6- CF₃ 288 na H methyl methyl bromo5-cyano, 6- CF₃ 289 na H methyl methyl methyl 5-cyano, 6- CF₃ 290 na Hmethyl methyl methyl 5-nitro, 6- CF₃ 291 na H methyl methyl cyano5-nitro, 6- CF₃ 292 na methyl- methyl methyl H 5-bromo, sulfonyl 6-CF₃293 na methyl- methyl methyl H 5-bromo sulfonyl 294 na H methyl methyl H5-bromo 295 na H methyl methyl cyano 5-cyano, 6- CF₃ 316 ± methyl-methyl —CH₂—S-ethyl H 5-bromo sulfonyl 317 −^((a)) methyl methyl—CH₂—S-ethyl methyl 5-cyano, 6- CF₃ 318 −^((a)) methyl methyl—CH₂—S-ethyl methyl 5-cyano, 6- CF₃ 319 ± H methyl —CH₂—SO-ethyl methyl5-cyano, 6- CF₃ 320 ± methyl- methyl —CH₂—S-ethyl H 5-(3- sulfonylchloro- phenyl) 321 ± H methyl —CH₂—S-ethyl H 5-(3- chloro- phenyl) 322± methoxy- methyl —CH₂—S-ethyl H 5-cyano, 6- methyl CF₃ 323 ± cyano-methyl —CH₂—S-ethyl H 5-cyano, 6- methyl CF₃ 324 ± H methyl —CH₂—S-ethyliodo 5-cyano, 6- CF₃ 325 ± H methyl —CH₂—S-ethyl —CC— 5-cyano, 6-Si(CH₃)₃ CF₃ 326 ± H methyl —CH₂—S-ethyl —CCH 5-cyano, 6- CF₃ 327 ± Htrifluoro- —CH₂—S-ethyl H 5-cyano, 6- methyl CF₃ 328 ± methoxy- Htrifluoromethyl H 5-cyano, 6- methyl CF₃ 329 ± H methyl trifluoromethylH 5-cyano, 6- CF₃ 330 ± H methyl trifluoromethyl iodo 5-cyano, 6- CF₃331 ± cyano- methyl trifluoromethyl H 5-cyano, 6- methyl CF₃ 332 ±methoxy- methyl trifluoromethyl H 5-cyano, 6- methyl CF₃ 333 ± methyl-methyl trifluoromethyl H 5-cyano, 6- thio- CF₃ methyl 334 + H methyltrifluoromethyl H 5-cyano, 6- CF₃ 335 − H methyl trifluoromethyl H5-cyano, 6- CF₃ 344 ± H methyl —CH₂—S-ethyl ethyl 5-cyano, 6- CF₃ 345−^((a)) H methyl trifluoromethyl chloro 5-cyano, 6- CF₃ 346 −^((a)) Hmethyl trifluoromethyl iodo 5-cyano, 6- CF₃ 347 −^((a)) H methyltrifluoromethyl —CC— 5-cyano, 6- Si(CH₃)₃ CF₃ 348 −^((a)) H methyltrifluoromethyl —CCH 5-cyano, 6- CF₃ 349 −^((a)) H methyl —CH₂—S-ethyliodo 5-cyano, 6- CF₃ 350 −^((a)) H methyl —CH₂—S-ethyl —CC— 5-cyano, 6-Si(CH₃)₃ CF₃ 351 −^(a)) H methyl —CH₂—S-ethyl —CCH 5-cyano, 6- CF₃ 352−^((a)) H methyl —CH₂—S-ethyl ethyl 5-cyano, 6- CF₃ 353 ± H methyl—CH₂—S-ethyl H 5-chloro 354 −^((a)) H methyl —CH₂—SO₂-ethyl ethyl5-cyano, 6- CF₃ 355 na H methyl methyl —CCH 5-cyano, 6- CF₃ 356 na Hmethyl methyl —CC— 5-cyano, 6- Si(C₃)₃ CF₃ 357 na H trifluoro-trifluoromethyl H 5-cyano, 6- methyl CF₃ 358 na methyl- trifluoro-trifluoromethyl H 5-cyano, 6- sulfonyl methyl CF₃ 394 ± H H —CH₂Cl H5-cyano, 6- CF₃ 397 +^((a)) H methyl —CH₂—SO₂-ethyl H 5-cyano, 6- CF₃398 +^((a)) H methyl —CH₂—S-ethyl iodo 5-cyano, 6- CF₃ 401 +^((a)) Hmethyl —CH₂—S-ethyl bromo 5-cyano, 6- CF₃ 402 ± methyl- methyl—CH₂—S-ethyl H 5-cyano sulfonyl 403 ± H methyl —CH₂—S-ethyl H 5-cyano404 ± H methyl —CH₂—SO₂-ethyl H 5-chloro, 6-CF₃ 405 na H methyl methyl H5,6- dichloro 406 ± H methyl —CH₂—S-ethyl chloro 5-chloro 407 ± H methyl—CH₂—SO₂-ethyl H 5-cyano, 6- CF₃ 408 ± H H —CH₂—S-methyl H 5-cyano, 6-CF₃ 409 na H methyl methyl —CH═CH₂ 5-chloro, 6-CF₃ 410 ± H H—CH₂—S-ethyl H 5-cyano, 6- CF₃ 411 ± H H —CH₂—S-ethyl iodo 5-cyano, 6-CF₃ 412 ± H H —CH₂—SO₂-ethyl H 5-cyano, 6- CF₃ 413 ± H H —CH₂—S-ethylbromo 5-cyano, 6- CF₃ 414 ± H methyl —CH₂—S-ethyl H 5-methyl, 6-CF₃ 415± H methyl —CH₂—S-ethyl H 5-cyano, 6- methyl, 7- iodo 426 ± H methyl—CH₂—O-(4- H 5-cyano, 6- cyano-phenyl) CF₃ 428 ± H methyl—CH₂—O-(3-nitro- H 5-cyano, 6- phenyl) CF₃ 429 ± H methyl —CH₂—O-(3-CF₃—H 5-cyano, 6- 4-cyano- CF₃ phenyl) 436 ± H methyl trifluoromethyl H5-cyano, 6- CF₃ 445 ± H methyl —CH₂—S-ethyl H 5-cyano, 6- methoxy 446 ±H methyl —CH₂—S-ethyl H 5-cyano, 6- methyl ^((a))Thestereo-configuration for these compounds was not experimentallydetermined. However, the compounds were made from stereospecificprecursors. More specifically, compounds #151, 155, 195, 231, 232, 242,247 and 250 were prepared from compound #150; compounds #156 and 241were prepared from compound #149; compounds #248, 249, 349, 350, 351,353 and 354 were prepared from compound #233; compound #345, 346, 347and 348 were prepared from compound #355. The listedstereo-configuration os therefore based on the stere-configuration ofthe precursor. ^((b))Compounds #113, 114, 116 and 117 were prepared witha single configuration at the S of the SO group, although relative andabsolute configurations were not determined.

TABLE 3 Compounds of Formula (I)

ID No * R¹ R² R³ R⁴ (R⁵)_(a) 253 ± H methyl —S-(4- H 5-chloro, 6-CF₃chlorophenyl) 268 ± H methyl —S-isopropyl H 5-nitro, 6-CF₃

TABLE 4 Compounds of Formula (I)

ID No * R⁶ (R⁵)_(a) 8 ± 4-chlorophenyl 5-nitro, 6-CF₃ 9 ± ethyl 5-nitro,6-CF₃

TABLE 5 Compounds of Formula (III)

ID No * R⁶ (R⁵)_(a) 1 ± cyclohexyl 5-CF₃ 2 ± phenyl 5-CF₃ 3 ±4-chlorophenyl 5-CF₃ 5 ± 4-fluorophenyl 5-CF₃ 6 ± ethyl 5-cyano

Additional representative compounds of the present invention are aslisted in Table 6 below.

TABLE 6

As used herein, unless otherwise noted, the term “halogen” shall meanchlorine, bromine, fluorine and iodine.

As used herein, unless otherwise noted, the term “alkyl”, whether usedalone or as part of a substituent group, includes straight and branchedchains. For example, alkyl radicals include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.Unless otherwise noted, “lower” when used with alkyl means a carbonchain composition of 1-4 carbon atoms.

As used herein, unless otherwise noted, the term “halogen substitutedlower alkyl” shall mean a lower alkyl group as defined above wherein oneor more of the hydrogen atoms is replaced with a halogen atom. Suitableexamples include, but are not limited to, trifluoromethyl,2,2,2-trifluoro-eth-1-yl, chloromethyl, fluoromethyl and the like.Similarly, the term “fluorinated lower alkyl” shall mean a lower alkylgroup as defined above wherein one or more of the hydrogen atoms isreplaced with a fluorine atom. Suitable examples include, but are notlimited to, fluoromethyl, fluoroethyl, trifluoromethyl,2,2,2-trifluoro-eth-1-yl, and the like.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, the term “cycloalkyl” shall meanany stable four to eight membered monocyclic, saturated ring system, forexample cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocylic aromatic groups such as phenyl, naphthyl, andthe like.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered, monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered, bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like.

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., cycloalkyl, aryl,heteroaryl, etc), that group may have one or more substituents,preferably from one to five substituents, more preferably from one tothree substituents, most preferably from one to two substituents,independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl-(C₁-C₆alkyl)-aminocarbonyl-(C₁-C₆alkyl)”substituent refers to a group of the formula

Under the standard nomenclature used throughout this disclosure,substituents on the core will be designated such that the X (or Y) atomis numbered 1 and the remaining ring atoms are numbered sequentially ina counterclockwise direction. For example, for compounds of formula (I),the substituents on the core shall be designated as bound at thefollowing positions of attachment:

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

-   -   AR=Androgen Receptor    -   BPH=Benign Prostatic Hyperplasia    -   Bu₄NHSO₄ or =Tetrabutyl ammonium hydrogen sulfate    -   TBAHS    -   DABCO=1,4-Diazabicyclo[2.2.2]octane    -   DCM=Dichloromethane    -   DIPEA or DIEA or =Diisopropylethylamine    -   iPr₂NEt    -   DHT=Dihydrotestosterone    -   DMAC=N,N-Dimethylacetamide    -   DMAP=4-N,N-Dimethylaminopyridine    -   DMEM/F12=Dulbecco's modified Eagle's medium/F12    -   DMF=N,N-Dimethylformamide    -   DMSO=Dimethylsulfoxide    -   DTT=Dithiothreitol    -   EDTA=Ethylene diamine tetraacetic acid    -   Et₂O=Diethyl ether    -   EtOAc=Ethyl acetate    -   EtOH=Ethanol    -   HPLC=High Pressure Liquid Chromatography    -   KOAc=Potassium Acetate    -   mCPBA=m-Chloro-peroxybenzoic acid    -   MeOH=Methanol    -   NBS=N-bromosuccinimide    -   NCS=N-chlorosuccinimide    -   NIS=N-iodosuccinimide    -   NMP=1-Methyl2-pyrrolidinone    -   NMR=Nuclear Magnetic Resonance    -   PdCl₂(PPh₃)₂=Bis(triphenylphosphine) Palladium (II) chloride    -   Pd₂(dba)₃=Tris[μ-[(1,2-η:4,5-η)-(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one]]dipalladium    -   PdCl₂(dppf)=1,1′-Bis(diphenylphosphino)ferrocenepalladium        chloride    -   Pd(OAc)₂=Palladium (II) acetate    -   Ph₃P=Triphenyl Phosphine    -   OTBS=t-Butyl-dimethyl silyloxy    -   OXONE®=Potassium monopersulfate triple salt    -   PBS=Phosphate-buffered saline    -   TBAF=Tetrabutylammonium fluoride    -   TE or TED Buffer=Tris HCl+EDTA (Tetraacetic Acid Ethylene        Diamine)    -   TEA or Et₃N=Triethylamine    -   THF=Tetrahydrofuran    -   TMS=Trimethylsilyl    -   Tris HCl=Tris[hydroxymethyl]aminomethyl hydrochloride

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes, but is not limited to, alleviation ofthe symptoms of the disease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto “pharmaceutically acceptable salts.” Other salts may, however, beuseful in the preparation of compounds according to this invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds include acid addition salts which may,for example, be formed by mixing a solution of the compound with asolution of a pharmaceutically acceptable acid such as hydrochloricacid, sulfuric acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, citric acid, tartaric acid, carbonic acid orphosphoric acid. Furthermore, where the compounds of the invention carryan acidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts, e.g., sodium or potassium salts; alkalineearth metal salts, e.g., calcium or magnesium salts; and salts formedwith suitable organic ligands, e.g., quaternary ammonium salts.Representative pharmaceutically acceptable salts include the following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichlorolactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I), compounds of formula(II) and/or compounds of formula (III) with a pharmaceuticallyacceptable carrier. Pharmaceutical compositions containing one or moreof the compounds of the invention described herein as the activeingredient can be prepared by intimately mixing the compound orcompounds with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending upon the desired route of administration(e.g., oral, parenteral). Thus for liquid oral preparations such assuspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,stabilizers, coloring agents and the like; for solid oral preparations,such as powders, capsules and tablets, suitable carriers and additivesinclude starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like. Solid oral preparations mayalso be coated with substances such as sugars or be enteric-coated so asto modulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared utilizing aqueous carriers along withappropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.01-500 mg and maybe given at a dosage of from about 0.05-500 mg/kg/day, preferably fromabout 0.05-10 mg/kg/day, more preferably from about 1.0-3.0 mg/kg/day.The dosages, however, may be varied depending upon the requirement ofthe patients, the severity of the condition being treated and thecompound being employed. The use of either daily administration orpost-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient of the present invention. The tablets or pills ofthe novel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders or conditions modulated by the androgenreceptor described in the present invention may also be carried outusing a pharmaceutical composition comprising any of the compounds asdefined herein and a pharmaceutically acceptable carrier. Thepharmaceutical composition may contain between about 0.01 mg and 500 mg,preferably about 10 to 100 mg, of the compound, and may be constitutedinto any form suitable for the mode of administration selected. Carriersinclude necessary and inert pharmaceutical excipients, including, butnot limited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixers, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders or conditions modulated by the androgenreceptor is required.

The daily dosage of the products may be varied over a wide range from0.01 to 500 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. An effectiveamount of the drug is ordinarily supplied at a dosage level of fromabout 0.01 mg/kg to about 500 mg/kg of body weight per day. Preferably,the range is from about 0.5 to about 10.0 mg/kg of body weight per day,most preferably, from about 1.0 to about 3.0 mg/kg of body weight perday. The compounds may be administered on a regimen of 1 to 4 times perday.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

Compounds of formula (I), (II) and (III) may be prepared according tothe processes outlined in the Schemes below.

Compounds of formula (I) wherein b is 0, c is 0 and X is NR¹, may beprepared according to the process outlined in Scheme 1 below.

Accordingly, a suitably substituted compound of formula (V), a knowncompound or compound prepared by known methods, is reacted with a sourceof iodine or bromine, such as NIS, ICI, NBS, Br₂, I₂ and the like, in anorganic solvent or mixture thereof, such as THF, methanol, acetic acid,THF/methanol, and the like, optionally in the presence of a catalyst,such as acetic acid (with ICI), toluene sulfonic acid (with NIS or NBS),and the like, to yield the corresponding compound of formula (VI),wherein Q is I or Br, respectively.

The compound of formula (VI) is reacted with mesyl chloride (oralternatively, with p-toluenesulfonyl chloride), in the presence of anorganic base such as pyridine, potassium t-butoxide, and the like, in anorganic solvent such as THF, pyridine, DMF, and the like, to yield thecorresponding compound of formula (VII).

The compound of formula (VII) is reacted with a suitably substitutedcompound of formula (VIII), a known compound or compound prepared byknown methods, in the presence of a catalyst such as PdCl₂(PPh₃)₂,Pd₂(dba)₃, PdCl₂(dppf), and the like, in the presence of CuI, in thepresence of an organic base, preferably, in the presence of a tertiaryamine base such as TEA, DIPEA, pyridine, and the like, in an organicsolvent such as THF, DMF, DMAC, and the like, to yield the correspondingcompound of formula (Ia).

The compound of formula (Ia) is optionally de-protected according toknown methods, for example, by reacting with a base such as NaOH, KOH,NaO(lower alkyl), and the like, in an organic solvent or mixture thereofsuch as methanol/water, ethanol/water, THF, and the like, to yield thecorresponding compound of formula (Ib). Alternatively, the compound offormula (Ia) is reacted with TBAF in an organic solvent such as THF,DMF, and the like, preferably at an elevated temperature of greater thanor equal to about 50° C., to yield the corresponding compound of formula(Ib).

Compounds of formula (II) wherein b is 0, c is 0 and X is NR¹ andcompounds of formula (III) wherein b is 0 and c is 0, may be similarlyprepared according to the process outlined in Scheme 1 above.

More particularly, compounds of formula (II) wherein b is 0, c is 0 andX is NR¹ may be prepared by substituting a suitably substituted compoundof formula (IX)

a known compound or compound prepared by known methods, for the compoundof formula (VIII), to yield the corresponding compound of formula (IIa)

The compound of formula (IIa) may be further optionally de-protectedaccording to known methods to yield the corresponding compound offormula (IIb) wherein R¹ is hydrogen.

Similarly, compounds of formula (III) may be prepared according to theprocess outlined in Scheme 1 by substituting a suitably substitutedcompound of formula (X)

a known compound or compound prepared by known methods, for the compoundof formula (V), to yield the corresponding compound of formula (IIIa)

The compound of formula (IIIa) may be further optionally de-protectedaccording to known methods to yield the corresponding compound offormula (IIIb) wherein R¹ is hydrogen.

Compounds of formula (I), compounds of formula (II) and compounds offormula (III) wherein b is 1 and/or c is 1 can be prepared according tothe process outlined in Scheme 1 by substituting a suitably substitutedcompound of formula (XI), (XII) or (XIII)

a known compound or compound prepared by known methods, for the compoundof formula (VIII).

Compounds of formula (I) wherein R⁴ is lower alkyl, more preferablymethyl, may be prepared according to the process outlined in Scheme 2.

Accordingly, a suitably substituted compound of formula (VI) is reactedwith a suitably substituted compound of formula (XIV), a known compoundor compound prepared by known methods, in the presence of a catalystsuch as palladium acetate, in the presence of a base such as potassiumacetate, DABCO, and the like, at an elevated temperature, preferably, atan elevated temperature of greater than or equal to about 70° C., morepreferably, at an elevated temperature of about 80° C., to yield thecorresponding compound of formula (Ic).

Compounds of formula (II) and compounds of formula (III) wherein R⁴ islower alkyl, preferably methyl, may be similarly prepared according tothe process outlined in Scheme 2. More specifically, compounds offormula (II) may be prepared by substituting a suitably substitutedcompound of formula (XV)

for the compound of formula (XIV). Similarly, compounds of formula (III)may be prepared by substituting a suitably substituted compound offormula (XVI)

for the compound of formula (VI).

Compounds of formula (I) wherein R⁴ is other than hydrogen or methyl,may be prepared according to the processes outlined in Schemes 3 and 4below.

Compounds of formula (I) wherein R⁴ is cyano may be prepared accordingto the process outlined in Scheme 3 below.

Accordingly, a suitably substituted compound of formula (Ib) is reactedwith a source of iodine, bromine or chlorine such as NIS, NBS, NCS, andthe like, in the presence of a base such as potassium t-butoxide, NaH,and the like, in an organic solvent such as THF, DMAC, NMP, and thelike, to yield the corresponding compound of formula (Id), wherein J isI, Br or Cl, respectively.

The compound of formula (Id) wherein J is Br or I is reacted with CuCN,in an organic solvent such as DMF, DMAC, NMP, and the like, to yield thecorresponding compound of formula (Ie).

Compounds of formula (I) wherein R⁴ is lower alkyl other than methyl,lower alkenyl or lower alkynyl may be prepared according to the processoutlined in Scheme 4.

The compound of formula (Id) wherein J is Br or I, is reacted with asuitably substituted compound of formula (XVII), a known compound orcompound prepared by known methods, in the presence of a catalyst suchas PdCl₂(PPh₃)₄, Pd₂(dba)₃, PdCl₂(dppf), and the like, in the presenceof CuI, in the presence of an organic base, preferably a tertiary aminebase such as TEA, DIPEA, pyridine, and the like, to yield thecorresponding compound of formula (XVIII).

The compound of formula (XVIII) is reacted with a reagent such as TBAF,K₂CO₃, NaO(lower alkyl), and the like, in an organic solvent such asTHF, MeOH, EtOH, and the like, to yield the corresponding compound offormula (If).

One skilled in the art will recognize that the compound of formula (If)may be further optionally reduced with a suitable reducing agent such asH₂ gas in the presence of a catalyst such as Pd on carbon, Pt on carbon,Lindlar's catalyst, and the like, in an organic solvent such as ethylacetate, methanol, ethanol, and the like, to yield the correspondingcompound of formula (I) wherein the alkynyl group is converted to thecorresponding alkenyl (i.e. by selecting the reducing conditions topartially reduce the triple bond, or alkyl (i.e. by selecting thereducing conditions to fully reduce the triple bond).

Alternatively, the compound of formula (Id) is reacted with a suitablysubstituted compound of formula (XIX), a known compound or compoundprepared by known methods, in the presence of a catalyst such asPd(PPh₃)₄, and the like, in the presence of an inorganic salt such aslithium chloride, and the like, to yield the corresponding compound offormula (Ig) (For example, see Tetrahedron 58(51) 2002 pp. 10181-10188).The compound of formula (Ig) may then be further, optionally reduced, asdescribed above, to yield the corresponding compound wherein the loweralkenyl is converted to the corresponding lower alkyl (other thanmethyl).

One skilled in the art will further recognize that compounds of formula(II) and compounds of formula (III) wherein R⁴ is other than hydrogenmay be similarly prepared according to the processes outlined in Scheme3 and 4 above, by substituting a suitably substituted compound offormula (IIb) or a suitably substituted compound of formula (IIIb)

for the compound of formula (Ib) in Scheme 3; or by substituting asuitably substituted compound of formula (IId) or a suitably substitutedcompound of formula (IIId)

for the compound of formula (Id) in Scheme 4.

Compounds of formula (I), particularly compounds of formula (I) whereinR² is —(CH₂)₁₋₄—S(O)₀₋₂—R⁶ may be prepared according to the processoutlined in Scheme 5.

Accordingly, a suitably substituted compound of formula (VII), wherein Qis I or Br, is reacted with a suitably substituted compound of formula(XVIII), wherein G is a selected from the group consisting of H, Cl,OTBS and S—R⁶, a known compound or compound prepared by known methods,in the presence of a catalyst such as PdCl₂(PPh₃)₂, PdCl₂(dppf),Pd₂(dba), and the like, in the presence of CuI, in the presence of anorganic base, preferably, a tertiary amine base such as TEA, DIPEA,pyridine, and the like, in an organic solvent such as THF, DMF, DMAC,and the like, to yield the corresponding compound of formula (Ih).

The compound of formula (Ih) is optionally de-protected according toknown methods to yield the corresponding compound of formula (Ij). Forexample, when G is H or S—R⁶, the compound of formula (Ih) may bereacted with a base such as NaOH, KOH, and the like, in an organicsolvent or mixture thereof such as methanol/water, ethanol/water,THF/water, and the like, to yield the corresponding compound of formula(Ij) wherein G is H or —S—R⁶, respectively. Alternatively, when G isOTBS, the compound of formula (Ih) may be reacted with a base such asNaOH, KOH, and the like, in an organic solvent or mixture thereof suchas methanol/water, ethanol/water, THF/water, and the like, to yield thecorresponding compound of formula (Ij) wherein the OTBS group (G) isconverted to an —OH group.

Wherein the compound of formula (Ij) G is S—R⁶, the compound of formula(Ij) is further optionally reacted with an oxidizing reagent such asOXONE®/TBAHS, mCPBA, and the like, in an organic solvent or mixturethereof such as ethyl acetate/water, methanol/water, DCM, ethyl acetate,and the like, to yield the corresponding compound of formula (Ik).

Alternatively, wherein the compound of formula (Ij) G is S—R⁶, thecompound of formula (Ij) is further optionally reacted with a compoundof formula (XIX), a known compound or compound prepared by knownmethods, wherein E is Cl, Br or I, preferably, in the presence of a basesuch as NaH, potassium t-butoxide, and the like, in an organic solventsuch as THF, DMF, NMP, and the like, to yield the corresponding compoundof formula (Im).

One skilled in the art will recognize that the compound of formula (Im)may be further optionally reacted with an oxidizing reagent such asOXONE®/TBAHS, mCPBA, and the like, in an organic solvent or mixturethereof such as ethyl acetate/water, methanol/water, DCM, ethyl acetate,and the like, to yield the corresponding compound wherein the —S— of the—(CH₂)₁₋₄—S—R⁶ substituent group is oxidized to the corresponding —SO—or —SO₂— group.

One skilled in the art will further recognize that compounds of formula(III) wherein R² is —(CH₂)₁₋₄—S(O)₀₋₂—R⁶ may similarly be preparedaccording to the process outlined in Scheme 5 by substitution of asuitably substituted compound of formula (XX)

for the compound of formula (VII).

One skilled in the art will further recognize that compounds of formula(I) and compounds of formula (III) wherein R² is selected from—(CH₂)₁₋₄—O—R⁶, —(CH₂)₁₋₄—NH—R⁶ or —(CH₂)₁₋₄—N(lower alkyl)-R⁶ may besimilarly prepared according to the process outlined in Scheme 5 above,by selecting and substituting a suitably substituted compound of formula(XVIII) wherein G is replaced with an —O—R⁶, —NH—R⁶ or —N(loweralkyl)-R⁶ group, respectively.

Compound of formula (I) wherein R² is selected from the group consistingof —(CH₂)₁₋₄—S(O)₀₋₂—R⁶ and wherein R⁶ is an optionally substituted arylor an optionally substituted heteroaryl may alternatively be preparedfrom the corresponding compound of formula (Ih) wherein G is Cl,according to the process outlined in Scheme 6.

Accordingly, a suitably substituted compound of formula (Ih) wherein Gis Cl, is reacted with a suitably substituted compound of formula (XXI),a known compound or compound prepared by known methods, in the presenceof a base such as NaOCH₃, NaO(lower alkyl), TEA, and the like, in anorganic solvent such as methanol, ethanol, THF, and the like, to yieldthe corresponding compound of formula (Ik).

The compound of formula (Ik) is reacted with a suitably selectedoxidizing agent such as OXONE®/TBAHS, mCPBA, and the like, in an organicsolvent or mixture thereof such as ethyl acetate/water, methanol/water,DCM, ethyl acetate, and the like, to yield the corresponding compound offormula (Im).

One skilled in the art will further recognize that compounds of formula(III) wherein R² is —(CH₂)₁₋₄—S(O)₀₋₂—R⁶ may similarly be preparedaccording to the process outlined in Scheme 6 by substitution of asuitably substituted compound of formula (IIIh)

wherein G is Cl, for the compound of formula (IIIh).

Compounds of formula (I) wherein R² is selected from —(CH₂)₁₋₄—O—C(O)—R⁶may be prepared according to the process outlined in Scheme 7.

Accordingly, a suitably substituted compound of formula (XXII) (preparedas previously described in Scheme 5, de-protecting a compound of formula(Ih) wherein G is OTBS) is reacted with a suitably substituted acidchloride, a compound of formula (XXIII), a known compound or compoundprepared by known methods, in the presence of an organic base,preferably, a tertiary amine base such a TEA, DIPEA, pyridine, and thelike, in an organic solvent such as THF, DCM, acetonitrile, and thelike, to yield the corresponding compound of formula (In).

One skilled in the art will further recognize that compounds of formula(III) wherein R² is —(CH₂)₁₋₄—O—C(O)—R⁶ may similarly be preparedaccording to the process outlined in Scheme 7 by substitution of asuitably substituted compound of formula (IIIh)

wherein G is OTBS, for the compound of formula (Ih).

Compounds of formula (I) wherein R¹ is other than hydrogen or wherein R⁷is other than hydrogen may be prepared according to the process outlinedin Scheme 8.

Accordingly, a suitably substituted compound of formula (Ib), is reactedwith a suitably substituted compound of formula (XXIV), wherein V is Br,Cl or I, a known compound or compound prepared by known methods, in thepresence of a base such as potassium t-butoxide, sodium hydride, and thelike, in an organic solvent such as THF, DMF, DMAC, and the like, toyield a mixture of the corresponding compounds of formula (Ip) and (Iq).

One skilled in the art will further recognize that compounds of formula(II) and compounds of formula (III) wherein R¹ is other than hydrogen orR⁷ is other than hydrogen, may be similarly prepared according to theprocess outlined in Scheme 8, with substitution of suitably substitutedcompounds of formula (IIb) or (IIIb)

for the compound of formula (Ib).

One skilled in the art will further recognize that compounds of formula(I), compounds of formula (II) and/or compounds of formula (III) whereinb is other than 0 and/or wherein c is other than 0 may similarly beprepared according to any of the processes outlined in Schemes 2-8 byselecting and substituting suitably substituted reagents for thosedisclosed herein.

Compounds of formula (I) and compounds of formula (II) wherein X is 0may be similarly prepared according to the processes described herein,with appropriate selection and substitution of suitable startingmaterial.

For example, compounds of formula (I) may be prepared according to theprocess outlined in Scheme 1 by substituting a suitably substitutedcompound of formula (XXV)

for the compound of formula (V).

Compounds of formula (I) and compounds of formula (II) wherein X is Smay be prepared according to the process outlined in Scheme 9.

Accordingly, a suitably substituted compound of formula (XXVI), a knowncompound or compound prepared by known methods, is reacted with iodineor a source or iodine, according to known methods (for example, J. Het.Chem., 15(2), 1978, pp 337-342), to yield the corresponding compound offormula (XXVII).

The compound of formula (XXVI) or the compound of formula (XXVII) isreacted according to known methods, to yield the corresponding compoundof formula (XXVIII), wherein M is Li, Mg, Zn, Cu, and the like, andwherein the compound of formula (XXVIII) is preferably not isolated. Thecompound of formula (XXVIII) is reacted with a suitably substitutedcompound of formula (XXIX), a known compound or compound prepared byknown methods, according to known methods (for example, J. Med. Chem.46(4), 2003, pp 532-541) to yield the corresponding compound of formula(Ir).

One skilled in the art will recognize that compounds of formula (I)wherein X is S and wherein R⁴, b and/or c are other then hydrogen and 0,respectively, may be similarly prepared according to the processoutlined in Scheme 9 above by selecting and substituting suitablysubstituted reagents for the compounds of formula (XXVI).

One skilled in the art will further recognize that compounds of formula(II) wherein X is S may be similarly prepared according to the processoutlined in scheme 9 above by selecting and substituting a suitablysubstituted cyclic ketone, for example a compound of formula (XXX)

for the compound of formula (XXIX).

Compounds of formula (IX) are known compounds or compounds which may beprepared by known methods. For example, compounds of formula (IX) may beprepared according to the process outlined in Scheme 10.

Accordingly, a suitably substituted compound of formula (XXX), a knowncompound or compound prepared by known methods, is reacted with acompound of formula (XXXI), wherein W is Br, Cl or I, a known compoundor compound prepared by known methods, in an anhydrous organic solventsuch as THF, diethyl ether, and the like, to yield the correspondingcompound of formula (IX).

Compounds of formula (XVIII) are known compounds or compounds which maybe prepared by known methods. For example, compounds of formula (XVIII)may be prepared according to the process outlined in Scheme 11.

Accordingly, a suitably substituted compound of formula (XXXII), a knowncompound or compound prepared by known methods, wherein G is selectedfrom the group consisting of H, Cl, OTBS and S—R⁶, is reacted with acompound of formula (XXXI) wherein W is Br, Cl or I, a known compound,in an anhydrous organic solvent such as THF, diethyl ether, and thelike, to yield the corresponding compound of formula (XVIII).

Compounds of formula (XI) and compounds of formula (XII) wherein R² is—CH₂—S—R⁶ may alternatively be prepared according to the processoutlined in Scheme 12.

Accordingly, a suitably substituted compound of formula (XXXIII), aknown compound or compound prepared by known methods, is reacted with(CH₃)₃SI, in the presence of a base such as sodium hydride, potassiumhydride, and the like, in an organic solvent such as DMF, DMSO, and thelike, to yield the corresponding compound of formula (XXXIV).

The compound of formula (XXXIV) is reacted with Li—CC—TMS, a knowncompound or compound prepared by known methods (for example by reactingHCC—TMS with butyl lithium), to yield a mixture of the compound offormula (XXXV) and (XXXVI).

The compound of formula (XXXV) and/or the compound of formula (XXXVI)(isolated or in a mixture) is reacted with a reagent such as TBAF,K₂CO₃, NaO(lower alkyl), and the like, in an organic solvent such asTHF, methanol, ethanol, and the like, to yield the correspondingcompound of formula (XIIa) and/or the corresponding compound of formula(XIa) (isolated or in a mixture), respectively.

Compounds of formula (XIV) wherein R² is —(CH₂)₁₋₄—S—R⁶ may be preparedaccording to the process outlined in Scheme 13.

The compound of formula (XXXVII), a known compound or compound preparedby known methods, is reacted with a suitably substituted compound offormula (XXXVIII), a known compound or compound prepared by knownmethods, in an anhydrous organic solvent such as THF, diethyl ether, andthe like, to yield the corresponding compound of formula (XIVa).

The following General Procedures are set forth to aid in theunderstanding of the invention, providing examples for completingselected steps in the synthesis of the compound of the presentinvention. These synthesis procedures are not intended and should not beconstrued to limit in any way the invention set forth in the claimswhich follow thereafter. In the general schemes described below,

represents phenyl or a six membered heteroaryl ring structure containingone to two N atoms.

Example A Oxidation

A suitably substituted sulfide is dissolved in a 1:1 mixture ofdichloromethane and water and stirred rapidly. A catalytic amount oftetrabutylammonium hydrogensulfate is employed as a phase-transfercatalyst (PTC), added to the solution in an amount between about 1% andabout 20%. Next 3 equivalents of OXONE® are added and the solution isstirred overnight at room temperature. The layers are separated and theaqueous layer is extracted with dichloromethane. The combined organiclayers are washed with water and/or 10% sodium thiosulfate solution,then brine, dried over magnesium sulfate, filtered, and evaporated toyield a residue which is purified by column chromatography.

Example B De-Protection

A suitably substituted protected indole derivative or intermediate isdissolved in methanol and about 1 to about 4 equivalents of sodiumhydroxide solution (1 to 4 M) or lithium hydroxide dissolved in aminimal amount of water. The reaction mixture is stirred at temperaturein the range of between about 0° C. to about 50° C., the reaction isallowed to proceed for about 0.5 hour to about overnight, and then thereaction mixture is concentrated under vacuum. Water is added to theresidue and the solution is acidified with 1N hydrochloric acidsolution. The aqueous solution is extracted twice with diethyl ether andthe diethyl ether extracts are dried over magnesium sulfate, filtered,and concentrated under vacuum to yield a residue. The residue ispurified by column chromatography.

Example C Sonogashira

A suitably R⁰ substituted protected aniline (wherein R⁰ is a lower alkylsuch as methyl, phenyl or tolyl) is added to a round-bottom flask alongwith about 5 to about 10 mole % of bis(triphenylphosphine) palladium(II)chloride and about 10 to about 25 mole % of copper iodide. The flask isfitted with a septum attached to an argon, nitrogen or alternative inertgas inlet. The solvent—tetrahydrofuran or dimethylformamide—is added viasyringe followed by about 1.5 to about 2 equivalents of triethylamine ordiethylamine. The solution is stirred for about 1 to about 30 minutesand a suitably substituted alkyne is added either neat or in a smallamount of the solvent used in the reaction. The reaction is allowed toproceed for about 3 to about 24 hours. The solution is evaporated andthe residue is purified by column chromatography.

Example D Alkyne

A 0.5 M solution of ethynylmagnesium bromide is cooled down in an icebath under an argon atmosphere. A suitably substituted ketone is addedin portions slowly via syringe and the reaction is allowed to proceedovernight. A solution of saturated ammonium chloride is added to thereaction and extracted twice with ethyl ether. The ethyl ether extractsare dried over magnesium sulfate, filtered, and evaporated to yield anoil. The oil is purified using a Kugelrohr or by column chromatography.

Example E Iodo Protected Aniline: Pyridine Method, Step 1

A suitably substituted aniline or derivative is dissolved in pyridine.About equivalents of methanesulfonyl chloride is added and the solutionis stirred overnight at room temperature. The solution is evaporatedunder vacuum and ethyl acetate is added to the residue and thendecanted. This is done multiple times. The washes are combined and thenwashed with water, 1N hydrochloric acid solution, water and brine, thendried over magnesium sulfate, filtered and evaporated to yield a solid.

Example F Iodo Protected Aniline: Pyridine Method, Step 2

A solution of a suitably substituted bismethanesulfonate derivative inmethanol is heated to about 50° C. in a water bath. Lithium hydroxide orsodium hydroxide (about 1.5 equivalents) in a minimal amount of water isadded. The solution is stirred for about two hours at about 50° C. thenallowed to proceed overnight at about room temperature. The solvent isremoved under vacuum and water is added. The solution is acidified with1N hydrochloric acid solution and a solid precipitates out. The solid isfiltered off and washed with water and pentane. The solid is then takenup in ethyl acetate or diethyl ether and the organic solution is washedwith water, dried over magnesium sulfate, filtered, evaporated to yielda solid.

Example G Iodo Protected Aniline: Potassium t-butoxide Route

A suitably substituted iodoaniline or derivative is dissolved in THF andcooled in an ice bath under argon. Potassium t-butoxide (1.0M in THF)(about 3.2 equivalents) is added dropwise via syringe in portions overabout one-half hour. The solution is stirred for about one-half hour andabout 1.6 equivalents of methanesulfonyl chloride are added all at once.The reaction is allowed to go overnight. Water and 1N hydrochloric acidare added to the solution and then extracted twice with diethyl ether.The diethyl ether extracts are washed with water and brine, then driedover magnesium sulfate, filtered, and evaporated to yield a residuewhich is purified by column chromatography as necessary.

Example H Iodination

A suitably substituted aniline or derivative is dissolved in a 1:1mixture of THF and methanol. About 1.1 equivalents of N-iodosuccinimideare then added, followed by addition of about 5 mol % ofp-toluenesulfonic acid monohydrate. The solution is stirred overnight,then concentrated and diethyl ether is added. The solution is washedwith water twice to remove succinimide, then washed with brine, driedover magnesium sulfate, filtered, evaporated to yield a solid which istriturated with pentane or hexanes to remove iodine. The solid is thenagain filtered and washed with pentane or hexanes and dried.

Example I Sulfide Displacement

A suitably substituted alkyl chloride is dissolved in methanol. Theanion of the substituted arylthio is prepared by dissolving the thiol inabout an equimolar amount of 0.5M sodium methoxide in methanol. Thethiolate solution (about 2 equivalents) is added to the alkyl chloridein methanol and stirred overnight. The solution is concentrated and 1NHCl is added, followed by extraction twice with ethyl ether. The etherextracts are dried over magnesium sulfate, filtered, and evaporated toyield a residue. The residue is purified by column chromatography.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products may be listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 11-(3,4-Dichloro-phenylsulfanyl)-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

To a solution of1-chloro-2-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol(1.0 g, 2.5 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) wasadded 3,4-dichlorobenzenethiol (0.64 mL, 5.0 mmol) followed by 0.5Msodium methoxide in methanol (10 mL, 5.0 mmol). The reaction mixture wasstirred at room temperature overnight. The next day the solvent wasevaporated and water was added and the solution was acidified with 1NHCl solution. The solution was extracted three times with ethyl acetate.The combined extracts were washed with brine, dried over magnesiumsulfate, filtered, and evaporated to yield a yellow oil. The crudematerial (oil) was purified by column chromatography three times. Thesolvent systems used in the purification were of the following order: 5%diethyl ether in dichloromethane, 1% diethyl ether in dichloromethane,and 60% diethyl ether in pentane. The first product that came off wasthe tertiary sulfide of the title compound as a byproduct. The secondproduct collected from the column was the title compound, a yellowsolid.

MH−1=464, MH+23=488

Example 21-Chloro-2-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

To a 500 mL round-bottom flask were addedN-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (4.3 g,10.48 mmol), bis(triphenylphosphine) palladium (II) chloride (0.74 g,1.048 mmol) and copper (I) iodide (0.40 g, 2.096 mmol). The solids weredissolved in tetrahydrofuran (100 ml) and triethylamine (2.2 mL, 15.72mmol). The reaction mixture was then evacuated using an adapter fittedto the flask connected to a manifold with vacuum and nitrogen lines.Argon was bubbled into the solution. The flask was then filled withnitrogen and the process was repeated five times. To the reactionmixture was then added 1-chloro-2-methyl-but-3-yn-2-ol in a small amountof tetrahydrofuran (1.61 g, 11.53 mmol). The reaction was stirredovernight under nitrogen. The reaction mixture was concentrated anddiethyl ether was added. Some material was observed to have crashed out.The mixture was filtered through Celite and the Celite was washed withdiethyl ether. The filtrate was evaporated and the residue pre-absorbedonto silica gel. The residue was purified by column chromatographyeluting with 70% dichloromethane in pentane to yield the title compoundas a yellow solid.

MH−1=321, (loss of methanesulfonyl protecting group on indole ring)

Example 3 1-Chloro-2-methyl-but-3-yn-2-ol

A solution of ethynyl magnesium bromide (0.5M in tetrahydrofuran, 200mL, 100 mmol) was cooled in an ice bath under argon. Chloroacetone (8mL, 100 mmol) was added in portions using a syringe. The solution wasallowed to stir overnight at room temperature under argon. The reactionwas worked-up by adding saturated ammonium chloride solution (100 mL).The solution was extracted twice with diethyl ether and the extractswashed with brine, dried over magnesium sulfate, filtered and evaporatedto a brown oil. The oil was purified on a Kugelrohr as the temperatureof the oven was ramped slowly to 70° C. under vacuum. Two bulbs wereused to collect the distillate, which was collected to yield the titlecompound as an oil.

Example 4 N-(2-Iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide

A solution ofN-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-bismethanesulfonamide (18.85g, 38.61 mmol) in methanol (250 mL) was heated to 50° C. in a waterbath. Lithium hydroxide (1.39 g, 57.92 mmol) in a minimal amount ofwater was added. The solution was stirred for 2 hours, maintaining thetemperature between 50 and 60° C., then let stir overnight at roomtemperature. The solvent was evaporated off and water was added. Thewater was decanted leaving a brown oil. The water was acidified to pH 1using concentrated hydrochloric acid. An off-white solid precipitatedwas formed, it was filtered and washed with water and pentane and dried.The solid was dissolved in ethyl acetate and the solution washed withwater, brine, dried over magnesium sulfate, filtered, and evaporated toyield the title compound as an orange solid.

MH−=409

Example 5N-(2-Iodo-4-nitro-5-trifluoromethyl-phenyl)-bismethanesulfonamide

To a solution of 2-iodo-4-nitro-5-trifluoromethyl-phenylamine (23.4 g,70.5 mmol) in pyridine (80 mL) was added methanesulfonyl chloride (27.3mL, 352.5). The reaction was allowed to proceed overnight at roomtemperature. The pyridine was evaporated and ethyl acetate was addedmultiple times to the residue and decanted off to yield a brown solid.The brown solid was then filtered off and washed with ethyl acetate. Thecombined washes were washed with water, 1N hydrochloric acid solution,water, brine, dried over magnesium sulfate, filtered, and evaporated toyield the title compound as a brown solid.

Example 6 2-Iodo-4-nitro-5-trifluoromethyl-phenylamine

5-Amino-2-nitrobenzotrifluoride (16.25 g, 78.8 mmol) was dissolved intetrahydrofuran (100 mL) and methanol (100 mL) and to this solution wasadded p-toluenesulfonic acid (0.18 g, 0.95 mmol) and N-iodosuccinimide(17.8 g, 78.8 mmol). The solution was stirred all day. N-iodosuccinimide(0.78 g, 3.47 mmol) and p-toluenesulfonic acid (0.2 g, 1.05 mmol) werethen added and the solution stirred overnight at room temperature undernitrogen. The solution was concentrated under vacuum to a small volume.Water (200 mL) was added to the reaction mixture and a brown solidprecipitated out. The solid was filtered and washed with water, thendissolved in ethyl acetate (100 mL) and diethyl ether (60 mL). Theorganic solution was washed with 10% sodium thiosulfate solution (50mL). This created an emulsion which was alleviated by adding diethylether and water and filtering undissolved material. The layers wereseparated and the organic layer was washed with 10% sodium thiosulfatesolution (50 mL), water was then added to the aqueous layer and thelayers separated. The organic layer was washed with brine (50 mL), driedover magnesium sulfate, filtered, and evaporated to yield the titlecompound as a brown solid that was dried under vacuum.

MH−=331

Example 71-(3,4-Dichloro-phenylsulfanyl)-2-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

A solution of 3,4-dichlorobenzenethiol (0.04 mL, 0.29 mmol) in DMF (3mL) was prepared. To this solution was added diisopropylethylamine (0.05mL, 0.29 mmol) after which the solution turned yellow.1-Methanesulfonyl-2-(2-methyl-oxiranyl)-5-nitro-6-trifluoromethyl-1H-indole(53 mg, 0.145 mmol) in DMF (0.5 mL) was added via syringe and thereaction mixture stirred. After 2 hours the solution was added to waterand 1N HCl. An off-white solid was filtered off, washed with water, andallowed to dry. The solid was purified by column chromatography elutingwith dichloromethane to yield the title compound as an oil.

MH+Na=566

Example 81-Methanesulfonyl-2-(2-methyl-oxiranyl)-5-nitro-6-trifluoromethyl-1H-indole

A solution of2-isopropenyl-1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indole(2.55 g, 7.32 mmol) in acetonitrile (18 mL) was prepared. Most of thesolid was observed to dissolve in the acetonitrile. Water was added (2mL) to the reaction mixture resulting in some cloudiness.N-bromosuccinimide was added (1.46 g, 8.20 mmol) followed by additionalacetonitrile (5 mL). The reaction was allowed to proceed overnight.Water was added and the solution was extracted twice with diethyl ether.The diethyl ether extracts were washed with water, then brine, driedover magnesium sulfate, filtered, and evaporated to yield a residue. Theresidue was purified by column chromatography eluting with 30, 50, and57% diethyl ether in pentane. Some mixed fractions with product wereevaporated down and triturated with diethyl ether to yield the titleproduct as a white solid which was filtered off.

MH+Na=387

MH−=285 (loss of methanesulfonyl group)

Example 92-Isopropenyl-1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indole

This compound was prepared using the general Sonagashira conditions asdescribed in general Example C, starting fromN-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (9.0 g,21.9 mmol) and 2-methyl-1-buten-3-yne (6.25 mL, 65.7 mmol) to yield thetitle compound as a reddish-brown solid.

Example 10 1-(4-Chloro-phenylsulfanyl)-2-(1H-indol-2-yl)-propan-2-ol

A solution of1-(4-chloro-phenylsulfanyl)-2-(1-methanesulfonyl-1H-indol-2-yl)-propan-2-ol(0.18 g, 0.46 mmol) in methanol (10 mL) was prepared. 1M Sodiumhydroxide (3.2 mL, 3.2 mmol) was then added to the reaction mixture. Thereaction did not go to completion after stirring overnight at roomtemperature. 3N Sodium hydroxide solution was then added and thesolution became milky white. The solution gradually became clear.Diethyl ether was added and the layers separated. The aqueous layer wasacidified with 1N HCl and extracted with diethyl ether. The diethylether extracts were washed with 1N HCl solution, water and brine, driedover magnesium sulfate, filtered, and evaporated to yield crude product.The crude material was purified by column chromatography eluting with 30and 50% diethyl ether/pentane to yield the title compound as a solid.

MH−=316

Example 111-(4-Chloro-phenylsulfanyl)-2-(1-methanesulfonyl-1H-indol-2-yl)-propan-2-ol

A solution of 1-chloro-2-(1-methanesulfonyl-1H-indol-2-yl)-propan-2-ol(0.36 g, 1.25 mmol) in methanol (12 mL) was prepared. To this solutionwas added 4-chlorothiophenol (0.36 g, 2.50 mmol) dissolved into 0.5 Msodium methoxide in methanol solution (5 mL, 2.50 mmol). The reactionwas stirred overnight at room temperature. The solvent was evaporatedand 1N HCl was added to the residue. The solution was extracted twicewith diethyl ether and the diethyl ether extracts dried over magnesiumsulfate, filtered and evaporated to yield a yellow oil. The oil waspurified by column chromatography eluting with 30% diethyl ether/pentaneto yield the title compound as a clear oil.

MH+Na=418

Example 12 1-Chloro-2-(1-methanesulfonyl-1H-indol-2-yl)-propan-2-ol

This compound was prepared using the general Sonagashira procedure asdescribed in General Example C, fromN-(2-iodo-phenyl)-methanesulfonamide (1.65 g, 5.55 mmol) and1-chloro-2-methyl-but-3-yn-2-ol (0.79 g, 6.66 mmol) to yield a brownoil.

Example 13 N-(2-Iodo-phenyl)-methanesulfonamide

This compound was prepared using the general pyridine method, step 2 asdescribed in General Procedures Example F, starting fromN-(2-iodo-phenyl)-bismethanesulfonamide (19.27 g, 51.36 mmol) to yieldthe title compound as a brown solid.

MH−=296

Example 14 N-(2-Iodo-phenyl)-bismethanesulfonamide

This compound was prepared using the general pyridine method, step 1, asdescribed in the General Procedure Example E, starting from2-iodoaniline (20 g, 91.31 mmol) to yield the title compound as a brownsolid.

MH−=296, loss of methanesulfonyl group

Example 152-(5-Chloro-6-trifluoromethyl-1H-indol-2-yl)-1-(4-fluoro-benzenesulfonyl)-propan-2-ol

To a solution of2-(5-chloro-6-trifluoromethyl-1H-indol-2-yl)-1-(4-fluoro-phenylsulfanyl)-propan-2-ol(0.42 g, 1.04 mmol) in dichloromethane (10 mL) was added water (10 mL).The solution was stirred rapidly and tetrabutylammonium hydrogensulfate(12 mg, 0.035 mmol) was added followed by OXONE® (1.02 g, 1.66 mmol).The reaction mixture turned bright yellow and was allowed to proceedovernight at room temperature. The reaction mixture was diluted withwater and dichloromethane, the layers were separated and the aqueouslayer was extracted with dichloromethane. The combined organic layerswere washed with water, twice with 10% sodium thiosulfate solution andbrine, then dried over magnesium sulfate. The magnesium sulfate wasfiltered off and the filtrate was concentrated and pre-absorbed ontosilica gel and purified by column chromatography eluting with 80%diethyl ether/pentane to yield the title product as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.88 (brs, 1H), 7.75 dd, J=5.0, 8.8 Hz, 2H),7.70 (s, 1H), 7.53 (s, 1H), 7.05 (t, J=8.4, 2H), 6.04 (s, 1H), 4.76 (s,1H), 3.71 (d, J=14.6, 1H), 3.65 (d, J=14.5, 1H), 1.85 (s, 3H)

MH−=434.

Example 161-Ethanesulfinyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-oland1-Ethanesulfonyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

These compounds were prepared using the general oxidation procedure asdescribed in the General Procedures Example A, employing less OXONE®(0.35 g, 0.57 mmol). The starting material was1-ethylsulfanyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol(Assigned stereochemistry is R) (0.4 g, 1.1 mmol). The crude materialwas purified by column chromatography eluting with 3% methanol indiethyl ether. The first compound that came off was Compound #156, whichwas isolated as a solid.

MH+23=403

The next compound that came off the column was Compound #155, which wasisolated as a solid.

MH+23=387

Example 171-Ethylsulfanyl-2-(5-fluoro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

This compound was prepared using the general de-protection procedure asdescribed in the General Procedure Example B. The starting material usedwas1-ethylsulfanyl-2-(5-fluoro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol(0.8 g, 2.0 mmol) and the base used was 4M sodium hydroxide (1 mL, 4.0mmol). The product was obtained as a solid.

MH+=304 which is a loss of water

Example 181-Ethylsulfanyl-2-(5-fluoro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

This compound was prepared using the general Sonagashira procedure asdescribed in the General Procedures Example C. The starting material wasN-(4-fluoro-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (0.77 g,2.0 mmol) and 1-ethylsulfanyl-2-methyl-but-3-yn-2-ol (0.29 g, 2.0 mmol),reacted to yield the title compound as a golden oil.

MH+Na=422

Example 19N-(4-Fluoro-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide

This compound was prepared using the general pyridine method, step 2 asdescribed in the General Procedure Example F. The starting material wasN-(4-fluoro-2-iodo-5-trifluoromethyl-phenyl)-bismethanesulfonamide (8.2g, 17.8 mmol) which was reacted to yield the title compound as an orangesolid.

MH−=382

Example 20N-(4-Fluoro-2-iodo-5-trifluoromethyl-phenyl)-bismethanesulfonamide

This compound was prepared using the general pyridine procedure, step 1as described in the General Procedure Example E. The starting materialused was 4-fluoro-2-iodo-5-trifluoromethyl-phenylamine (5.6 g, 18.36mmol), which was reacted to yield the title compound as a solid.

MH−=382, loss of methanesulfonyl group

Example 21 4-Fluoro-2-iodo-5-trifluoromethyl-phenylamine

This compound was prepared using the standard iodination procedure, asdescribed in General Procedures Example H, to yield the title compoundas a reddish-brown oil.

MH+=306

Example 222-(5-Amino-6-trifluoromethyl-1H-indol-2-yl)-1-ethylsulfanyl-propan-2-ol

A solution of1-ethylsulfanyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol(0.35 g, 1.0 mmol) in ethanol (20 mL) was prepared. To the solution wasthen added saturated ammonium chloride solution (20 mL). Indium wasadded (1.15 g, 10 mmol) and the reaction heated to reflux. Afterone-half hour the reaction was complete. The reaction mixture wasfiltered through Celite and the Celite washed with water and diethylether. The layers were separated and the aqueous layer extracted withdiethyl ether. The organic layers were dried over magnesium sulfate,filtered, and evaporated to yield a residue. The residue was dissolvedin dichloromethane and purified by column chromatography eluting with1:1 diethyl ether/hexanes to yield the title compound as a solid.

MH+=319

Example 232-(2-Ethylsulfanyl-1-methoxy-1-methyl-ethyl)-5-nitro-6-trifluoromethyl-1H-indole

This compound was prepared using the general de-protection procedure, asdescribed in General Procedures Example. The starting material used was2-(2-ethylsulfanyl-1-methoxy-1-methyl-ethyl)-1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indole(0.17 g, 0.39 mmol). The base used was 4N sodium hydroxide (0.19 mL,0.77 mmol). The title compound was obtained as a yellow solid.

M+23=385

Example 242-(2-Ethylsulfanyl-1-methoxy-1-methyl-ethyl)-1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indole

This compound was prepared using the standard Sonagashira procedure asdescribed in General Procedures Example C. The starting material wasN-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (0.34 g,0.82 mmol) and 4-ethylsulfanyl-3-methoxy-3-methyl-but-1-yne (0.13 g,0.82 mmol), reacted to yield the title compound as a yellow film.

Example 25 4-Ethylsulfanyl-3-methoxy-3-methyl-but-1-yne

1-Ethylsulfanyl-2-methyl-but-3-yn-2-ol (0.29 g, 2.0 mmol) was added to amixture of sodium hydride (60% dispersion in mineral oil, 88 mg, 2.2mmol) in dimethylformamide (5 mL) under argon. Iodomethane (0.12 mL, 2.0mmol) was then added to the reaction mixture via syringe and the mixtureallowed to stir overnight. The mixture was poured onto water andextracted twice with diethyl ether. The diethyl ether extracts werewashed with water and brine, dried over magnesium sulfate, filtered, andevaporated to yield a yellow oil. The oil was purified by columnchromatography eluting with dichloromethane to yield the title compoundas a clear liquid.

Product does not mass.

Example 262-Ethanesulfinyl-1-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-ethanol

This compound was prepared using the general oxidation procedure asdescribed in General Procedures Example B, starting from2-ethylsulfanyl-1-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-ethanol(0.36 g, 1.08 mmol) to yield the title compound as a solid.

MH+23(Na)=373, MH−=349

Example 272-Ethylsulfanyl-1-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-ethanol

This compound was prepared using the general de-protection proceduredescribed in General Procedures Example B, starting from2-ethylsulfanyl-1-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-ethanol(1.52 g, 3.69 mmol) and 4M sodium hydroxide as base (1.8 mL, 7.38 mmol)to yield the title compound as a bright yellow solid.

MH−=333, MH+23(Na)=357.

Example 282-Ethylsulfanyl-1-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-ethanol

This compound was prepared using the general Sonagashira procedure asdescribed in General Procedures Example C, starting fromN-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (1.89 g,4.6 mmol) and 1-ethylsulfanyl-but-3-yn-2-ol (0.6 g, 4.6 mmol), reactedto yield the title compound as a yellow solid.

MH+23(Na)=435

Example 29 Ethylsulfanyl-but-3-yn-2-ol

This compound was prepared from the general alkyne procedure asdescribed in General Procedures Example D, starting from 0.5Methynylmagnesium bromide (25 mL, 12.58 mmol) andethylsulfanyl-acetaldehyde (1.31 g, 12.58 mmol), reacted to yield thetitle compound as a yellow oil.

Example 302-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol

This compound was prepared using the standard de-protection procedure,as described in General Procedure Example B, starting from2-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol(0.65 g, 1.31 mmol) and using 4N sodium hydroxide as base (1 mL, 4.0mmol) to yield the title compound as a solid.

MH−=415, MH+23=439

Example 312-(1-Methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol

This compound was prepared using the general Sonagashira procedure asdescribed in General Procedures Example C, reactingN-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (0.62 g,1.5 mmol) and 3-(2,2,2-Trifluoro-ethylsulfanylmethyl)-pent-1yn-3-ol(0.32 g, 1.5 mmol) to yield the title compound as a yellow sticky oil.

MH+23=517, MH−=415, loss of methanesulfonyl group

Example 322-(5-Chloro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol

This compound was prepared using the standard de-protection procedurefrom, as described in General Procedures Example B, reacting2-(5-chloro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol(0.24 g, 0.50 mmol) and using 4N sodium hydroxide as a base (0.37 mL,0.50 mmol) to yield the title compound as a yellow sticky oil.

MH−=404

Example 332-(5-Chloro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol

This compound was prepared using the standard Sonagashira procedure asdescribed in General Procedures Example C, reacting fromN-(4-chloro-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (0.60 g,1.5 mmol) and 3-(2,2,2-Trifluoro-ethylsulfanylmethyl)-pent-1yn-3-ol(0.32 g, 1.5 mmol) to yield the title compound as a yellow sticky oil.

MH−=404, loss of methanesulfonyl group

Example 342-(3-Chloro-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethanesulfonyl)-butan-2-ol

A solution of2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethanesulfonyl)-butan-2-ol(100 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was prepared. To thissolution was added N-chlorosuccinimide (33 mg, 0.25 mmol). The solutionwas stirred overnight at room temperature. Water was added and thesolution extracted twice with diethyl ether. The diethyl ether extractswere dried over magnesium sulfate, filtered, and evaporated to yield ayellow oil. The oil was dissolved in diethyl ether and purified bycolumn chromatography eluting with diethyl ether to yield the titlecompound as a yellow powder.

MH+23=505, MH−=481

Example 352-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethanesulfonyl)-butan-2-ol

This compound was prepared using the general oxidation procedure asdescribe in General Procedures Example A. The starting material used was2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethanesulfanyl)-butan-2-ol(0.25 g, 0.61 mmol), which was reacted to yield the title compound as ayellow, fluffy solid.

M+23=471

Example 362-(5-Fluoro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol

This compound was prepared using the general de-protection procedure asdescribe in General Procedures Example B, reacting2-(5-fluoro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol(0.59 g, 1.26 mmol) and using 4N sodium hydroxide as base (1 mL, 4.0mmol) to yield the title compound as a solid.

MH−=388

Example 372-(5-Fluoro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol

This compound was prepared using the general Sonagashira procedure asdescribe in General Procedures Example C, reactingN-(4-fluoro-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (0.57 g,1.5 mmol) and 3-(2,2,2-trifluoro-ethylsulfanylmethyl)-pent-1yn-3-ol(0.32 g, 1.5 mmol) to yield the title compound as a brown oil.

MH+Na=490, MH−=388, loss of methanesulfonyl group

Example 381-Butylsulfanyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

This compound was prepared using the general de-protection procedure asdescribe in General Procedures Example B. The starting material used was1-butylsulfanyl-2-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol(0.53 g, 1.16 mmol). The base that was used was 4N sodium hydroxidesolution (1 mL, 4 mmol). The title compound was obtained as a yellowsticky oil.

MH−=375

Example 391-Butylsulfanyl-2-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

This compound was prepared using the general Sonagashira procedure asdescribe in General Procedures Example C, reactingN-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (0.82 g,2.0 mmol) and 3-methyl-hept-1-yn-3-ol (0.34 g, 2.0 mmol) to yield thetitle compound as a yellow oil.

MH+23=477

Example 40 1-Butylsulfanyl-2-methyl-but-3-yn-2-ol

This compound was prepared using the general alkyne procedure asdescribe in General Procedures Example D, reacting 0.5M ethynylmagnesiumbromide (35.6 mL, 17.78 mmol) and hexan-2-one (2.6 g, 17.78 mmol) toyield the title compound as a yellow liquid.

Example 41 1-Butylsulfanyl-propan-2-one

A solution of 1-butanethiol (2.1 mL, 20.0 mmol) in methanol (133 mL) wasprepared and cooled in an ice bath under an argon atmosphere. 1M Sodiumhydroxide was then added (20 mL, 20 mmol), followed by addition ofchloroacetone (1.9 mL, 24.0 mmol). The reaction solution was stirredcold for two hours and then concentrated on a rotary evaporator. Waterwas added and the mixture extracted twice with diethyl ether. Thediethyl ether extracts were dried over magnesium sulfate, filtered, andevaporated to yield a yellow oil. The oil was used without furtherpurification.

Example 422-(6-Chloro-5-fluoro-1H-indol-2-yl)-1-ethylsulfanyl-propan-2-ol

To a solution of2-(6-chloro-5-fluoro-1-methanesulfonyl-1H-indol-2-yl)-1-ethylsulfanyl-propan-2-ol(0.30 g, 0.82 mmol) in methanol (10 mL) was added 4M sodium hydroxidesolution (0.4 mL). The reaction was allowed to proceed overnight at roomtemperature. Complete reaction was not achieved, so additional 1M sodiumhydroxide solution (1 mL) was added and the reaction mixture was heatedto 50° C. The reaction mixture was kept at 50° C. for two hours thenallowed to stir overnight at room temperature. The reaction mixture wasconcentrated and to the concentrate was added 1N hydrochloric acidsolution and water. The mixture was extracted twice with ethyl ether.The extracts were dried over Mg₂SO₄, filtered, and evaporated to yield aresidue. The residue was purified by column chromatography eluting withdichloromethane to yield the title compound as a yellow oil.

MH−=286

¹H NMR (400 MHz, CDCl₃) δ 8.56 (brs, 1H), 7.35 (q, J=6.1 Hz, 1H), 2.57(q, J=7.2 Hz, 2H), 1.05 (t, J=7.2 Hz, 3H).

Example 432-(6-Chloro-5-fluoro-1-methanesulfonyl-1H-indol-2-yl)-1-ethylsulfanyl-propan-2-ol

To a 50 mL round-bottom flask were addedN-(5-chloro-4-fluoro-2-iodo-phenyl)-methanesulfonamide (0.30 g, 1.0mmol), bis(triphenylphosphine) palladium(II) chloride (35 mg, 0.05 mmol)and copper (I) iodide (19 mg, 0.1 mmol). The flask was fitted with aseptum and stirred under argon. Tetrahydrofuran (5 mL) and triethylamine(0.28 mL, 2.0 mmol) were then added via syringe.1-Ethylsulfanyl-2-methyl-but-3-yn-2-ol (0.14 g, 1.0 mmol) intetrahydrofuran (1 mL) was added via syringe and the reaction maintainedwith stirring at 50-60° C. for four hours. The solution was evaporatedand the residue purified by column chromatography using dichloromethaneas solvent to yield the title compound as a brown oil.

MH+Na=388, MH− shows a loss of water at 348

Example 44 1-Ethylsulfanyl-2-methyl-but-3-yn-2-ol

A solution of 0.5M ethynyl magnesium bromide (60 mL, 30 mmol) was cooledin an ice bath under argon. (Ethylthio)acetone (3.55 g, 30 mmol) wasadded dropwise via syringe. The reaction mixture was stirred overnightat room temperature. The reaction mixture was then poured onto asaturated ammonium chloride solution and then extracted twice withdiethyl ether, dried over magnesium sulfate, filtered, and evaporated toyield a yellow oil. The oil was purified by column chromatographyeluting with dichloromethane to yield the title compound as a yellowliquid.

Example 452-(2-Ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-5-carbonitrile

This compound was prepared using the general de-protection procedure asdescribe in General Procedures Example B, reacting2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-1-methanesulfonyl-6-trifluoromethyl-1H-indole-5-carbonitrile(219 mg, 0.54 mmol) and using 4M sodium hydroxide (0.40 mL, 1.62 mmol)as the base, to yield the title compound as a white solid.

MH−=327

Example 462-(2-Ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-1-methanesulfonyl-6-trifluoromethyl-1H-indole-5-carbonitrile

This compound was prepared using the general Sonagashira procedure asdescribe in General Procedures Example C, reactingN-(4-cyano-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (1.0 g,2.56 mmol) and 1-ethylsulfanyl-2-methyl-but-3-yn-2-ol (0.37 g, 2.56mmol) to yield the title compound as a yellow sticky oil.

MH−=327, loss of methanesulfonyl group. MH+23(Na)=429

Example 47 1-Cyclopentylsulfanyl-propan-2-one

Cyclopentyl mercaptan (6.72 mL, 62.8 mmoL) in THF (50 mL) was treatedwith NaH (60%, 69.1 mmoL, 2.76 g) at 0° C. After bubbling ceased,chloroacetone (5.0 mL, 62.8 mmoL) was added into the reaction mixturevia syringe slowly. The reaction mixture was then stirred at 0° C. for 2hrs. The solvent was then removed and water and Et₂O were added. TheEt₂O layer was washed with brine, dried over Na₂SO₄ and concentrated toyield the title compound as an oil.

¹H NMR (CDCl₃, 400 MHz) δ 3.22 (s, 2H), 2.95 (m, 1H), 2.28 (s, 3H),2.05˜1.48 (m, 8H).

Example 48 1-Isopropylsulfanyl-propan-2-one

Isopropyl mercaptan (5.83 mL, 62.8 mmoL) in THF (50 mL) was treated withNaH (60%, 69.1 mmoL, 2.76 g) at 0° C. After bubbling ceased,chloroacetone (62.8 mmoL, 5 mL) was added into the reaction mixture viasyringe slowly. The reaction mixture was then stirred at 0° C. for 2hrs. The solvent was then removed and water and Et₂O were added. TheEt₂O layer was washed with brine, dried over Na₂SO₄ and concentrated toyield the title compound as an oil.

¹H NMR (CDCl₃, 400 MHz) δ 3.25 (s, 2H), 2.95 (m, 1H), 2.30 (s, 3H), 1.20(d, J=12.0 Hz, 3H), 1.15 (d, J=12.0 Hz, 3H).

Example 49 1-(2,2,2-Trifluoro-ethylsulfanyl)-propan-2-one

2,2,2-Trifluoroethanethiol (5.59 mL, 62.8 mmoL) in THF (50 mL) wastreated with NaH (60%, 69.1 mmoL, 2.76 g) at 0° C. After bubblingceased, chloroacetone (62.8 mmoL, 5 mL) was added into the reactionmixture via syringe slowly. The reaction mixture was then stirred at 0°C. for 2 hrs. The solvent was then removed and water and Et₂O wereadded. The Et₂O layer was washed with brine, dried over Na₂SO₄ andconcentrated to yield the title compound as an oil.

¹H NMR (CDCl₃, 400 MHz) δ 3.40 (s, 2H), 3.15 (abq, J=12.0 Hz, 2H), 2.31(s, 3H).

Example 50 1-Isopropylsulfanyl-2-methyl-but-3-yn-2-ol

Ethynyl magnesium bromide (0.5 M in THF, 12.12 mmoL, 25 mL) was addeddropwise into a solution of the compound prepared as in Example 48 (0.80g, 6.06 mmoL) at 0° C. After addition, the reaction mixture was stirredfor another 30 min at 0° C. Saturated NH₄Cl was added to quench thereaction. THF was removed and Et₂O was added. The aqueous phase wasextracted with Et₂O and the combined organic layer was washed withbrine, dried and concentrated to yield the crude title compound as aclear oil. The crude material was purified using column chromatography(silica gel, 4:1 hexanes:EtOAc as eluent) to yield the title compound asa colorless oil.

¹H NMR (CDCl₃, 400 MHz) δ 3.18 (m, 1H), 3.05 (d, J=10.5 Hz, 1H), 2.72(d, J=10.5 Hz, 1H), 2.42 (s, 1H), 2.38 (s, 1H), 1.55 (s, 3H), 1.28 (d,J=13.5 Hz, 3H), 1.24 (d, J=13.5 Hz, 3H).

Example 51 1-Cyclopentylsulfanyl-2-methyl-but-3-yn-2-ol

Ethynyl magnesium bromide (0.5 M in THF, 12.12 mmoL, 25 mL) was addeddropwise into a solution of the compound prepared as in Example 47 (1.0g, 6.33 mmoL) at 0° C. After addition, the reaction mixture was stirredfor another 30 min at 0° C. Saturated NH₄Cl was added to quench thereaction. THF was removed and Et₂O was added. The aqueous phase wasextracted with Et₂O and the combined organic layer was washed withbrine, dried and concentrated to give the crude title compound as aclear oil. The crude material was purified using column chromatography(silica gel, 4:1 hexanes:EtOAc as eluent) to yield the title compound asa colorless oil.

¹H NMR (CDCl₃, 400 MHz) δ 3.30 (m, 1H), 3.21 (d, J=11.0 Hz, 1H), 2.75(d, J=11.0 Hz, 1H), 2.42 (s, 1H), 2.05 (m, 2H), 1.80 (m, 2H), 1.55 (s,3H), 1.60˜1.40 (m, 4H).

Example 52 2-Methyl-1-(2,2,2-trifluoro-ethylsulfanyl)-but-3-yn-2-ol

Ethynyl magnesium bromide (0.5 M in THF, 12.12 mmoL, 25 mL) was addeddropwise into a solution of the compound prepared as in Example 49 (1.05g, 6.10 mmoL) at 0° C. After addition, the reaction mixture was stirredfor another 30 min at 0° C. Saturated NH₄Cl was added to quench thereaction. THF was removed and Et₂O was added. The aqueous phase wasextracted with Et₂O and the combined organic layer was washed withbrine, dried and concentrated to yield the crude title compound as aclear oil. The crude material was purified using column chromatography(silica gel, 4:1 hexanes:EtOAc as eluent) to yield the title compound asa colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 3.40 (m, 1H), 3.25 (m, 1H), 3.10 (abq, J=12.5Hz, 1H), 2.85 (abq, J=12.5 Hz, 1H), 2.78 (s, 1H), 2.54 (s, 1H), 1.60 (s,3H).

Example 53 1-Ethylsulfanyl-2-methyl-pent-3-yn-2-ol

(Ethylthio)acetone (3.0 g, 25.4 mmoL) was treated dropwise withCH₃CCMgBr (0.5 M, 28.0 mmoL, 56 mL) at 0° C. After addition, thereaction was stirred for additional 30 min and then quenched withsaturated NH₄Cl. THF was removed in vacuo. Water and Et₂O were added andthe aqueous layer was exacted 3× with Et₂O. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to yield crude title product as a yellow oil. The crudematerial was then purified by column chromatography (silica gel,hexanes:EtOAc 6:1 as eluent) to yield the title compound as a colorlessoil.

¹H NMR (CDCl₃, 400 MHz) δ 3.48 (dd, J=10.5, 4.8 Hz, 1H), 3.10 (s, 1H),3.02 (d, J=15.0 Hz, 1H), 2.72 (dd, J=10.5, 2.0 Hz, 1H), 2.70 (d, J=15.0Hz, 1H), 1.86 (s, 3H), 1.52 (s, 3H), 1.25 (t, J=15.0 Hz, 3H).

Example 541-Benzylsulfanyl-2-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

The compound prepared as in Example 4 (500 mg, 1.32 mmoL), PdCl₂(Ph₃P)₂(186 mg, 0.265 mmoL), CuI (50 mg, 0.265 mmoL) and TEA (1 mL, 6.70 mmoL)in THF (10 mL) was degassed with N₂ for 5 min.Benzylsulfanyl-2-methyl-but-3-yn-2-ol, the compound prepared as inExamples 49-52 substituting phenylmethyl-thiol for trifluoroethanethiol(300 mg, 1.46 mmoL) was added dropwise into the reaction mixture viasyringe at room temperature. The reaction was stirred for 2 hrs. Thesolvent was then removed and Et₂O was added into the residue. Themixture was then filtrated through a pad of Celite and the filtrate waswashed with brine, dried over anhydrous Na₂SO₄, then concentrated toyield a crude brown oil. The crude material was purified using columnchromatography (silica gel, 3:1 hexanes:EtOAc as eluent) to yield thetitle compound as a yellow oil.

¹H NMR (CDCl₃, 400 MHz) δ 8.60 (s, 1H), 8.06 (s, 1H), 7.28˜7.18 (m, 5H),6.75 (s, 1H), 4.08 (s, 1H), 3.68 (s, 2H), 3.32 (s, 3H), 3.30 (d, J=12.0Hz, 1H), 3.12 (d, J=12.0 Hz, 1H), 1.78 (s, 3H)

MS (m/z): 489 (M+H)

Example 551-Benzylsulfanyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

The compound prepared as in Example 54 (565 mg, 1.16 mmoL) in 4 NNaOH/MeOH solution (2 mL) was stirred at room temperature for 30 min.The solvent was removed. CH₂Cl₂ and H₂O were added. The organic layerwas washed with brine and dried over anhydrous Na₂SO₄, then concentratedto yield a crude brown oil. The crude material was purified using columnchromatography (silica gel, 3:1 hexanes:EtOAc as eluent) to yield thetitle compound as a light yellow solid.

¹H NMR (CDCl₃, 400 MHz) δ 9.18 (br, s, 1H), 8.18 (s, 1H), 7.75 (s, 1H),7.35˜7.14 (m, 5H), 6.42 (s, 1H), 3.69 (s, 2H), 3.08 (d, J=10.5 Hz, 1H),2.92 (d, J=10.5 Hz, 1H), 1.62 (s, 3H)

MS (m/z): 411 (M+H)⁺, 433 (M+Na)⁺.

Example 561-Isopropylsulfanyl-2-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

The compound prepared as in Example 4 (225 mg, 0.595 mmoL), PdCl₂(Ph₃P)₂(84 mg, 0.119 mmoL), CuI (23 mg, 0.119 mmoL) and TEA (0.4 mL, 2.98 mmoL)in THF (10 mL) was degassed with N₂ for 5 min. The compound prepared asin Example 50 (300 mg, 1.46 mmoL) was added dropwise into the reactionmixture via syringe at room temperature. The reaction was stirred for 2hrs. The solvent was then removed and Et₂O was added into the residue.The mixture was then filtrated through a pad of Celite and the filtratewas washed with brine, dried over anhydrous Na₂SO₄, then concentrated toyield a crude brown oil. The crude material was purified using columnchromatography (silica gel, 3:1 hexanes:EtOAc as eluent) to yield thetitle compound as a yellow oil.

¹H NMR (CDCl₃, 400 MHz) δ 8.65 (s, 1H), 8.16 (s, 1H), 6.85 (s, 1H), 4.08(s, 1H), 3.50 (s, 3H), 3.48 (d, J=10.5 Hz, 1H), 3.15 (d, J=10.5 Hz, 1H),2.92 (m, J=11.0 Hz, 1H), 1.82 (s, 3H), 1.22 (d, J=11.0 Hz, 6H)

MS (m/z): 441 (M+H)⁺, 463 (M+Na)⁺.

Example 571-Isopropylsulfanyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

The compound prepared as in Example 56 (125 mg, 0.284 mmoL) in 4 NNaOH/MeOH solution (2 mL) was stirred at room temperature for 30 min.The solvent was removed. CH₂Cl₂ and H₂O were added. The organic layerwas washed with brine and dried over anhydrous Na₂SO₄, then concentratedto yield a crude brown oil. The crude material was purified using columnchromatography (silica gel, 3:1 hexanes:EtOAc as eluent) to yield thetitle compound as a light yellow solid.

¹H NMR (CDCl₃, 400 MHz) δ 9.28 (br, s, 1H), 8.22 (s, 1H), 7.78 (s, 1H),6.52 (s, 1H), 3.45 (br, s, 1H), 3.12 (s, 2H), 3.04 (d, J=10.5 Hz, 1H),2.82 (m, 1H), 2.65 (d, J=10.5 Hz, 1H), 1.68 (s, 3H), 1.25 (d, J=11.0 Hz,6H)

MS (m/z): 363 (M+H)⁺.

Example 582-(1-Methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-propan-2-ol

The compound prepared as in Example 4 (1.75 g, 4.63 mmoL), PdCl₂(Ph₃P)₂(650 mg, 0.93 mmoL), CuI (177 mg, 0.93 mmoL) and TEA (3.23 mL, 23.15mmoL) in THF (30 mL) were degassed with N₂ for 5 min. The compoundprepared as in Example 52 (917 mg, 4.63 mmoL) was added dropwise intothe reaction mixture via syringe at room temperature. The reaction wasstirred for 2 hrs. The solvent was then removed and Et₂O was added intothe residue. The mixture was then filtrated through a pad of Celite andthe filtrate was washed with brine, dried over anhydrous Na₂SO₄, thenconcentrated to yield a crude brown oil. The crude material was purifiedusing column chromatography (silica gel, 3:1 hexanes:EtOAc as eluent) toyield the title compound as a yellow oil.

¹H NMR (CDCl₃, 400 MHz) δ 8.62 (s, 1H), 8.11 (s, 1H), 6.82 (s, 1H), 4.05(s, 1H), 3.55 (d, J=10.5 Hz, 1H), 3.40 (s, 3H), 3.32 (d, J=10.5 Hz, 1H),3.25˜3.12 (m, 2H), 1.82 (s, 3H)

MS (m/z): 481 (M+H)⁺.

Example 592-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-propan-2-ol

The compound prepared as in Example 58 (1.45 g, 3.02 mmoL) in a 4NNaOH/MeOH solution (5 mL) was stirred at room temperature for 30 min.The solvent was removed. CH₂Cl₂ and H₂O were added. The organic layerwas washed with brine and dried over anhydrous Na₂SO₄, then concentratedto yield a crude brown oil. The crude material was purified using columnchromatography (silica gel, 3:1 hexanes:EtOAc as eluent) to yield thetitle compound as a light yellow solid.

¹H NMR (CDCl₃, 400 MHz) δ 9.25 (br, s, 1H), 8.21 (s, 1H), 7.80 (s, 1H),6.48 (s, 1H), 3.25 (d, J=11.0 Hz, 1H), 3.15 (d, J=11.0 Hz, 1H), 3.10(abq, J=10.5 Hz, 2H), 2.92 (s, 1H), 1.78 (s, 3H)

MS (m/z): 403 (M+H)⁺, 425 (M+Na)⁺.

Chiral Separation, CH₃CN as Eluent:

Peak 1, the (−) enantiomer

[α]_(D) ²⁰−54 (c 0.21, MeOH)

Peak 2, the (+) enantiomer

[α]_(D) ²⁰+56 (c 0.14, MeOH)

Example 601-Cyclopentylsulfanyl-2-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

The compound prepared as in Example 4 (460 mg, 0.94 mmoL), PdCl₂(Ph₃P)₂(132 mg, 0.188 mmoL), CuI (36 mg, 0.188 mmoL) and Et₃N (0.66 mL, 4.70mmoL) in THF (10 mL) were degassed with N₂ for 5 min. The compoundprepared as in Example 51 (190 mg, 1.034 mmoL) was added dropwise intothe reaction mixture via syringe at room temperature. The reaction wasstirred for 2 hrs. The solvent was then removed and Et₂O was added intothe residue. The mixture was then filtrated through a pad of Celite andthe filtrate was washed with brine, dried over anhydrous Na₂SO₄, thenconcentrated to yield a crude brown oil. The crude material was purifiedusing column chromatography (silica gel, 3:1 hexanes:EtOAc as eluent) toyield the title compound as a yellow oil.

¹H NMR (CDCl₃, 400 MHz) δ 8.55 (s, 1H), 8.05 (s, 1H), 6.81 (s, 1H), 4.02(s, 1H), 3.38 (d, J=11.5 Hz, 1H), 3.35 (s, 3H), 3.12 (d, J=11.5 Hz, 1H),3.08 (m, 1H), 1.75 (s, 3H), 1.70˜1.60 (m, 2H), 1.60˜1.35 (m, 4H)

MS (m/z): 468 (M+H)⁺, 490 (M+Na)⁺.

Example 611-Cyclopentylsulfanyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

The compound prepared as in Example 58 (395 mg, 0.848 mmoL) in a 4NNaOH/MeOH solution (5 mL) was stirred at room temperature for 30 min.The solvent was removed. CH₂Cl₂ and H₂O were added. The organic layerwas washed with brine and dried over anhydrous Na₂SO₄, then concentratedto yield a crude brown oil. The crude material was purified using columnchromatography (silica gel, 3:1 hexanes:EtOAc as eluent) to yield thetitle compound as a light yellow solid.

¹H NMR (CDCl₃, 400 MHz) δ 9.28 (br, s, 1H), 8.20 (s, 1H), 7.78 (s, 1H),6.45 (s, 1H), 3.35 (s, 1H), 3.20 (d, J=11.0 Hz, 1H), 3.05 (d, J=11.0 Hz,1H), 3.02 (m, 1H), 2.01 (m, 2H), 2.75 (m, 2H), 1.70 (s, 3H), 1.60˜1.45(m, 4H)

MS (m/z): 389 (M+H)⁺.

Example 622-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-propylsulfanyl-propan-2-ol

The compound prepared as in Example 4 (300 mg, 0.732 mmoL), PdCl₂(Ph₃P)₂(102 mg, 0.15 mmoL), CuI (29 mg, 0.15 mmoL) and Et₃N (0.26 mL, 1.83mmoL) in THF (5 mL) was degassed with N₂ for 5 min.2-Methyl-1-propylsulfanyl-but-3-yn-2-ol, the compound prepared as inExample 49-52 substituting propanethiol for trifluoroethanethiol (174mg, 1.1 mmoL) was added dropwise into the reaction mixture via syringeat room temperature. The reaction was stirred for 2 hrs. The solvent wasthen removed and Et₂O was added into the residue. The mixture was thenfiltrated through a pad of Celite and the filtrate was washed withbrine, dried over anhydrous Na₂SO₄, then concentrated to yield a brownoil. The crude material in 4N NaOH/MeOH solution (2 mL) was stirred atroom temperature for 30 min. The solvent was removed. CH₂Cl₂ and H₂Owere added. The organic layer was washed with brine and dried overanhydrous Na₂SO₄, then concentrated to yield a crude brown oil. Thecrude material was purified using column chromatography (silica gel, 3:1hexanes:EtOAc as eluent) to yield the title compound as a light yellowsolid.

¹H NMR (CDCl₃, 400 MHz) δ 9.26 (br, s, 1H), 8.22 (s, 1H), 7.79 (s, 1H),6.48 (s, 1H), 3.39 (s, 1H), 3.20 (abq, J=14.3 Hz, 1H), 3.05 (abq, J=14.3Hz, 1H), 2.46 (m, 2H), 1.69 (s, 3H), 1.58 (m, J=7.3 Hz, 2H), 0.94 (t,J=7.3 Hz, 3H)

MS (m/z): 363 (M+H)⁺.

Example 631-Ethylsulfanyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-butan-2-ol

The compound prepared as in Example 4 (300 mg, 0.732 mmoL), PdCl₂(Ph₃P)₂(102 mg, 0.15 mmoL), CuI (29 mg, 0.15 mmoL) and Et₃N (0.26 mL, 1.83mmoL) in THF (5 mL) was degassed with N₂ for 5 min.3-Ethylsulfanyl-but-3-yn-2-ol, the compound prepared as in Example 49-52substituting ethanethiol for trifluoroethanethiol and substituting1-bromobutan-2-one for chloroacteone (174 mg, 1.1 mmoL) was addeddropwise into the reaction mixture via syringe at room temperature. Thereaction was stirred for 2 hrs. The solvent was then removed and Et₂Owas added into the residue. The mixture was then filtrated through a padof Celite and the filtrate was washed with brine, dried over anhydrousNa₂SO₄, concentrated to yield a crude brown oil. The crude oil in 4NNaOH/MeOH solution (2 mL) was stirred at room temperature for 30 min.The solvent was removed. CH₂Cl₂ and H₂O were added. The organic layerwas washed with brine and dried over anhydrous Na₂SO₄, concentrated toyield a crude brown oil. The crude material was purified using columnchromatography (silica gel, 3:1 hexanes:EtOAc as eluent) to yield thetitle compound as a light yellow solid.

¹H NMR (CDCl₃, 400 MHz) δ 9.35 (br, s, 1H), 8.25 (s, 1H), 7.78 (s, 1H),6.45 (s, 1H), 3.40 (s, 1H), 3.21 (d, J=11.0 Hz, 1H), 3.05 (d, J=11.0 Hz,1H), 2.75 (m, 1H), 2.60 (m, 1H), 1.98 (m, J=11.0 Hz, 2H), 1.20 (t,J=11.0 Hz, 3H), 0.90 (t, J=11.0 Hz, 3H)

MS (m/z): 363 (M+H)⁺, 385 (M+Na)⁺.

Example 642-(1-Methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-4-methylsulfanyl-butan-2-ol

The compound prepared as in Example 4 (300 mg, 0.732 mmoL), PdCl₂(Ph₃P)₂(102 mg, 0.15 mmoL), CuI (29 mg, 0.15 mmoL) and Et₃N (0.25 mL, 1.83mmoL) in THF (5 mL) was degassed with N₂ for 5 min.3-Methyl-5-methylsulfanyl-pent-1-yl-3-ol, the compound prepared as inExample 52 substituting 4-methylsulfanyl-butan-2-one for1-(2,2,2-trifluoroethylsulfanyl)-propan-2-one, (174 mg, 1.10 mmoL) wasadded dropwise into the reaction mixture via syringe at roomtemperature. The reaction was stirred for 2 hrs. The solvent was thenremoved and Et₂O was added into the residue. The mixture was thenfiltrated through a pad of Celite and the filtrate was washed withbrine, dried over anhydrous Na₂SO₄, concentrated to yield a crude brownoil. The crude material was purified using column chromatography (silicagel, 3:1 hexanes:EtOAc as eluent) to yield the title compound as ayellow oil.

¹H NMR (CDCl₃, 400 MHz) δ 8.68 (s, 1H), 8.12 (s, 1H), 6.80 (s, 1H), 4.21(s, 1H), 2.78 (m, 1H), 2.68 (m, 1H), 2.20 (s, 3H), 2.05 (m, 2H), 1.82(s, 3H)

MS (m/z): 427 (M+H)⁺.

Example 654-Methylsulfanyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-butan-2-ol

The compound prepared as in Example 64 (264 mg, 0.62 mmoL) in a 4NNaOH/MeOH solution (5 mL) was stirred at room temperature for 30 min.The solvent was removed. CH₂Cl₂ and H₂O were added. The organic layerwas washed with brine and dried over anhydrous Na₂SO₄, concentrated toyield a crude brown oil. The crude material was purified using columnchromatography (silica gel, 3:1 hexanes:EtOAc as eluent) to yield thetitle compound as a light yellow solid.

¹H NMR (CDCl₃, 400 MHz) δ 9.55 (br, s, 1H), 8.15 (s, 1H), 7.72 (s, 1H),6.36 (s, 1H), 3.82 (s, 1H), 2.70 (m, 1H), 2.60 (m, 1H), 2.10 (s, 3H),1.98 (m, 2H), 1.65 (s, 3H)

MS (m/z): 371 (M+H)⁺, 719 (2M+Na)⁺.

Example 662-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(propane-1-sulfonyl)-propan-2-ol

The compound prepared as in Example 62 (75 mg, 0.21 mmoL) was dissolvedin CH₂Cl₂ (2 mL) and H₂O (2 mL). OXONE® (176 mg, 0.31 mmoL) and Bu₄NHSO₄(7 mg, 0.02 mmoL) were added in one portion into the reaction mixture.The mixture was stirred overnight. CH₂Cl₂ was added and the aqueousphase was extracted 3× with CH₂Cl₂. The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄, then concentrated toyield a crude pale solid. The crude material was purified using columnchromatography (silica gel, 1:1 hexanes:EtOAc as eluent) to yield thetitle compound as a white solid.

¹H NMR (CDCl₃, 400 MHz) δ 10.56 (s, br, 1H), 8.22 (s, 1H), 7.60 (s, 1H),6.56 (s, 1H), 5.07 (s, 1H0, 3.74 (abq, J=14.7 Hz, 1H), 3.48 (abq, J=14.7Hz, 1H), 2.80 (m, 2H), 1.88 (s, 3H), 1.81 (m, J=7.40 Hz, 2H), 0.94 (t,J=7.4 Hz, 3H)

MS (m/z): 395 (M+H)⁺.

Example 674-Methanesulfonyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-butan-2-oland4-Methanesulfinyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-butan-2-ol

The compound prepared as in Example 65 (125 mg, 0.36 mmoL) was dissolvedin CH₂Cl₂ (2 mL) and H₂O (2 mL). OXONE® (306 mg, 0.54 mmoL) and Bu₄NHSO₄(12 mg, 0.036 mmoL) were added in one portion into the reaction mixture.The mixture was stirred overnight. CH₂Cl₂ was added and the aqueousphase was extracted 3× with CH₂Cl₂. The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄, concentrated to yield acrude pale solid. The crude material was purified using columnchromatography (silica gel, 1:1 hexanes:EtOAc to 4:1 CH₂Cl₂:MeOH aseluent) to yield the title compounds as white solids.

4-Methanesulfonyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-butan-2-ol

¹H NMR (CDCl₃, 400 MHz) δ 9.70 (s, 1H), 8.20 (s, 1H), 7.75 (s, 1H), 6.48(s, 1H), 3.38 (br, s, 1H), 3.20 (m, 1H), 3.05 (m, 1H), 2.90 (s, 3H),2.45 (m, 2H), 1.72 (s, 3H)

MS (m/z): 403 (M+Na)⁺.

4-Methanesulfinyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-butan-2-ol

¹H NMR (CDCl₃, 400 MHz) δ 10.50 (s, br, 1H), 8.20 (s, 1H), 7.78 (s, 1H),6.42 (s, 1H), 2.95 (m, 1H), 2.75 (m, 1H), 2.60 (s, 3H), 2.55 (t, J=10.5Hz, 2H), 1.75 (s, 3H)

MS (m/z): 365 (M+H)⁺.

Example 681-Ethanesulfonyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-butan-2-ol

The compound prepared as in Example 63 (105 mg, 0.29 mmoL) was dissolvedin CH₂Cl₂ (2 mL) and H₂O (2 mL). OXONE® (306 mg, 0.54 mmoL) and Bu₄NHSO₄(10 mg, 0.03 mmoL) were added in one portion into the reaction mixture.The mixture was stirred overnight. CH₂Cl₂ was added and the aqueousphase was extracted 3× with CH₂Cl₂. The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄, then concentrated toyield a crude pale solid. The crude material was purified using columnchromatography (silica gel, 1:1 hexanes:EtOAc as eluent) to yield thetitle compound as a white solid.

¹H NMR (CDCl₃, 400 MHz) δ 9.42 (s, br, 1H), 8.21 (s, 1H), 7.80 (s, 1H),6.53 (s, 1H), 4.78 (s, 1H), 3.58 (d, J=12.0 Hz, 1H), 3.52 (d, J=12.0 Hz,1H), 2.80 (q, J=10.5 Hz, 2H), 2.22 (m, 1H), 2.05 (m, 1H), 1.32 (t,J=10.5 Hz, 3H), 085 (t, J=11.0 Hz, 3H)

MS (m/z): 395 (M+H)⁺.

2-(2-Ethanesulfonyl-1-hydroxy-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-5-carbonitrile,Compound #222

was similarly prepared according to the procedure described in Example68 above, by reacting2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-5-carbonitrile,Compound #217.

MS calculated for C₁₅H₁₅F₃N₂O₃S: 360.08. found 359 (M−H).

2-(2-Ethanesulfonyl-1-hydroxy-1-methyl-ethyl)-3-methyl-6-trifluoromethyl-1H-indole-5-carbonitrile,Compound #251

was similarly prepared according to the procedure described in Example68 above, by reacting2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-3-methyl-6-trifluoromethyl-1H-indole-5-carbonitrile,Compound #233.

MS calculated for C₁₆H₁₇F₃N₂O₃S: 374.09. found 373 (M−H).

Example 692-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethanesulfonyl)-propan-2-oland2-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethanesulfinyl)-propan-2-ol

The compound prepared as in Example 59 (201 mg, 0.5 mmoL) was dissolvedin CH₂Cl₂ (2 mL) and H₂O (2 mL). OXONE® (425 mg, 0.75 mmoL) and Bu₄NHSO₄(17 mg, 0.05 mmoL) were added in one portion into the reaction mixture.The mixture was stirred overnight. CH₂Cl₂ was added and the aqueousphase was extracted 3× with CH₂Cl₂. The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄, then concentrated toyield a crude pale solid. The crude material was purified using columnchromatography (silica gel, 1:1 hexanes:EtOAc first and then 4:1CH₂Cl₂:MeOH as eluent) to yield the title compounds as white solids.

2-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethanesulfonyl)-propan-2-ol

¹H NMR (CD₃OD, 400 MHz) δ 8.25 (s, 1H), 7.85 (s, 1H), 6.65 (s, 1H),4.45˜4.30 (m, 2H), 3.78 (d, J=10.5 Hz, 1H), 3.20 (d, J=10.5 Hz, 1H),1.90 (s, 3H)

MS (m/z): 457 (M+Na)⁺.

2-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethanesulfinyl)-propan-2-ol

¹H NMR (CD₃OD, 400 MHz) δ 8.25 (s, 1H), 7.90 (s, 1H), 6.70 (s, 1H), 4.05(m, 1H), 3.75 (m, 1H), 3.68 (d, J=13.0 Hz, 1H), 3.45 (d, J=13.0 Hz, 1H),1.86 (s, 3H)

MS (m/z): 441 (M+Na)⁺.

Example 702-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-phenylmethanesulfonyl-propan-2-oland2-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-phenylmethanesulfinyl-propan-2-ol

The compound prepared as in Example 55 (252 mg, 0.61 mmoL) was dissolvedin CH₂Cl₂ (2 mL) and H₂O (2 mL). OXONE® (380 mg, 0.67 mmoL) and Bu₄NHSO₄(5 mg, 0.06 mmoL) were added in one portion into the reaction mixture.The mixture was stirred overnight. CH₂Cl₂ was added and the aqueousphase was extracted 3× with CH₂Cl₂. The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄, then concentrated toyield a crude pale solid. The crude material was purified using columnchromatography (silica gel, 1:1 hexanes:EtOAc first and then 4:1CH₂Cl₂:MeOH as eluent) to yield the title compounds as white solids.

2-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-phenylmethanesulfonyl-propan-2-ol

¹H NMR (CD₃OD, 400 MHz) δ 8.25 (s, 1H), 7.88 (s, 1H), 7.42 (m, 2H), 7.35(m, 3H), 6.65 (s, 1H), 4.45 (s, 2H), 3.55 (abq, J=11.5 Hz, 2H), 3.30 (s,1H), 1.90 (s, 3H)

MS (m.z): 443 (M+H)⁺.

2-(5-Nitro-6-trifluoromethyl-1H-indol-2-yl)-1-phenylmethanesulfinyl-propan-2-ol

¹H NMR (CD₃OD, 400 MHz) δ 8.21 (s, 1H), 7.88 (s, 1H), 7.35˜7.25 (m, 5H),6.55 (s, 1H), 4.20 (d, J=11.0 Hz, 1H), 4.05 (d, J=11.0 Hz, 1H), 3.48 (d,J=11.5 Hz, 1H), 3.28 (d, J=11.5 Hz, 1H), 1.80 (s, 3H)

MS (m/z): 427 (M+H)⁺.

Example 715-Chloro-2-isopropenyl-1-methanesulfonyl-6-trifluoromethyl-1H-indole

N-(4-cyano-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide, thecompound prepared as in Examples 81-82 (2.28 g, 5.69 mmoL), PdCl₂(Ph₃P)₂(799 mg, 1.14 mmoL) and CuI (271 mg, 1.42 mmoL) in Et₃N (10 mL) wasdegassed with N₂ for 5 min. 2-Methyl-1-buten-3-yne (1.06 mL, 11.38 mmoL)was added dropwise into the reaction mixture via syringe at roomtemperature. The reaction was stirred for 3 hrs. The solvent was thenremoved and Et₂O was added into the residue. The mixture was thenfiltrated through a pad of Celite and the filtrate was washed withbrine, dried over anhydrous Na₂SO₄, then concentrated to yield a crudebrown oil. The crude material was purified using column chromatography(silica gel, 3:1 hexanes:EtOAc as eluent) to yield the title compound asa yellow oil.

¹H NMR (CDCl₃, 400 MHz) δ 8.40 (s, 1H), 7.72 (s, 1H), 6.51 (s, 1H), 5.31(s, 1H), 5.20 (s, 1H), 2.92 (s, 3H), 2.18 (s, 3H)

MS (m/z): 339 (M+H)⁺, 361 (M+Na)⁺.

Example 725-Chloro-1-methanesulfonyl-2-(2-methyl-oxiranyl)-6-trifluoromethyl-1H-indoleand1-(5-Chloro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-ethanone

The compound prepared as in Example 71 (210 mg, 0.622 mmoL) in CH₂Cl₂ (5mL) was treated with mCPBA (129 mg, 0.747 mmoL) at 0° C. The reactionmixture was slowly warmed to room temperature over 2 hrs. The mixturewas then washed with saturated NaHCO₃, brine and dried over anhydrousNa₂SO₄, then concentrated to yield a crude white solid. The crudematerial was purified using column chromatography (silica gel, 3:1hexanes:EtOAc as eluent) to yield the epoxide derivative as a whitesolid, along with the ketone by-product as a solid.

5-Chloro-1-methanesulfonyl-2-(2-methyl-oxiranyl)-6-trifluoromethyl-1H-indole

¹H NMR (CDCl₃, 400 MHz) δ 8.38 (s, 1H), 7.68 (s, 1H), 6.69 (s, 2H), 3.18(s, 3H), 3.05 (m, 2H), 1.78 (s, 3H)

MS (m/z): 380 (M+Na)⁺.

1-(5-Chloro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-ethanone

¹H NMR (CDCl₃, 400 MHz) δ 8.42 (s, 1H), 7.80 (s, 1H), 7.28 (s, 1H), 3.78(s, 3H), 2.62 (s, 3H)

MS (m/z): 341 (M+H)⁺.

Example 732-(5-Chloro-6-trifluoromethyl-1H-indol-2-yl)-1-(4-fluoro-phenylsulfanyl)-propan-2-ol

4-Fluoro-phenyl thiol (55 mg, 0.425 mmoL) was treated with NaH (60%, 17mg, 0.425 mmoL) in THF (2 mL) at 0° C. After 10 min.,5-chloro-1-methanesulfonyl-2-(2-methyl-oxiranyl)-6-trifluoromethyl-1H-indole,the epoxide derivative compound prepared as in Example 72 (100 mg, 0.425mmoL) in THF (1 mL) was added into the reaction via syringe. Thereaction was slowly warmed to room temperature. THF was removed and theresidue was partitioned between CH₂Cl₂ and water. The organic layer waswashed with brine and dried over anhydrous Na₂SO₄, then concentrated toyield a crude white solid. The crude material was purified using columnchromatography (silica gel, 3:1 hexanes:EtOAc as eluent) to yield thetitle compound as a white solid.

Example 742-Isopropenyl-1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indole

The compound prepared as in Example 4 (1.2 g, 2.08 mmoL), PdCl₂(Ph₃P)₂(290 mg, 0.415 mmoL), CuI (80 mg, 0.415 mmoL) and Et₃N (4.16 mmoL, 0.58mL) in THF (10 mL) was degassed with N₂ for 5 min.2-Methyl-1-buten-3-yne (0.3 mL, 3.12 mmoL) was added dropwise into thereaction mixture via syringe at room temperature. The reaction wasstirred for 3 hrs. The solvent was then removed and Et₂O was added intothe residue. The mixture was then filtrated through a pad of Celite andthe filtrate was washed with brine, dried over anhydrous Na₂SO₄, thenconcentrated to yield a crude brown oil. The crude material was purifiedusing column chromatography (silica gel, 4:1 hexanes:EtOAc as eluent) toyield the title compound as a yellow oil.

¹H NMR (CDCl₃, 400 MHz) δ 8.52 (s, 1H), 8.12 (s, 1H), 6.68 (s, 1H), 5.45(s, 1H), 5.32 (s, 1H), 3.08 (s, 3H)

MS (m/z): 349 (M+H)⁺.

Example 751-Methanesulfonyl-2-(2-methyl-oxiranyl)-5-nitro-6-trifluoromethyl-1H-indoleand1-(1-Methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-ethanone

The compound prepared as in Example 9 (955 mg, 2.74 mmoL) in CH₂Cl₂ (20mL) was treated with mCPBA (1.80 g, 8.22 mmoL) at 0° C. The reactionmixture was slowly warmed to room temperature over 2 hrs. The mixturewas then washed with saturated NaHCO₃, brine and dried over anhydrousNa₂SO₄, then concentrated to yield a crude white solid. The crudematerial was purified using column chromatography (silica gel, 4:1hexanes:EtOAc as eluent) to yield the epoxide derivative as a whitesolid, along with the ketone by-product as a solid.

1-Methanesulfonyl-2-(2-methyl-oxiranyl)-5-nitro-6-trifluoromethyl-1H-indole

¹H NMR (CDCl₃, 400 MHz) δ 8.68 (s, 1H), 8.35 (s, 1H), 6.85 (s, 1H), 3.31(s, 3H); 3.15 (m, 2H), 1.80 (s, 3H)

MS (m/z): 365 (M+H)⁺, 387 (M+Na)⁺.

1-(1-Methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-ethanone

¹H NMR (CDCl₃, 400 MHz) δ 8.71 (s, 1H), 8.32 (s, 1H), 7.40 (s, 1H), 3.75(s, 3H), 2.70 (s, 3H)

MS (m/z): 351 (M+H)⁺.

Example 761-Isobutylsulfanyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

NaH (28 mg, 0.70 mmoL) was added into 2-methylpropylthiol (0.06 mL, 0.56mmoL) in THF (2 mL) at 0° C. After bubbling ceased, the mixture wasstirred for additional 30 min.1-Methanesulfonyl-2-(2-methyl-oxiranyl)-5-nitro-6-trifluoromethyl-1H-indole,the epoxide derivative compound prepared as in Example 75, (100 mg, 0.28mmoL) in THF (2 mL) was added dropwise and the reaction was stirred,increasing the temperature from 0° C. to room temperature. SaturatedNH₄Cl was added to quench the reaction. THF was removed followed byaddition of CH₂Cl₂ and the aqueous phase was extracted 3× with CH₂Cl₂.The combined organic phase was washed with brine, dried over anhydrousNa₂SO₄, then concentrated to yield a crude pale solid. The crudematerial was purified using column chromatography (silica gel, 3:1hexanes:EtOAc as eluent) to yield the title compound as a white solid.

¹H NMR (CDCl₃, 400 MHz) δ 9.72 (br, s, 1H), 8.25 (s, 1H), 7.78 (s, 1H),6.60 (s, 1H), 3.88 (s, 1H), 2.50 (t, J=10.5 Hz, 1H), 2.24 (d, J=10.5 Hz,1H), 2.20 (d, J=11.0 Hz, 1H), 2.15 (d, J=11.0 Hz, 1H), 2.06 (d, J=10.5Hz, 1H), 1.75 (s, 3H), 0.90 (d, J=10.5 Hz, 6H)

MS (m/z): 377 (M+H)⁺.

Example 77 4-Bromo-2-iodo-5-trifluoromethyl-phenylamine

3-Trifluoro-4-bromo-aniline (5 g, 20.8 mmoL) in MeOH (10 mL) and THF (10mL) was treated with NIS (5.16 g, 22.9 mmoL) at room temperature. After2 hours, the reaction was quenched with saturated Na₂S₂O₃. The solventwas removed and the residue was partitioned between CH₂Cl₂ and water.The organic layer was washed with brine and dried over anhydrous Na₂SO₄,then concentrated to yield a crude white solid. The crude material waspurified using column chromatography (silica gel, 3:1 hexanes:EtOAc aseluent) to yield the title compound as a white solid.

¹H NMR (CDCl₃, 400 MHz) δ 7.88 (s, 1H), 6.98 (s, 1H), 4.45˜4.18 (br, s,2H).

Example 782-(2-Ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-3-methyl-6-trifluoromethyl-1H-indole-5-carbonitrile

4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (250 mg, 0.84 mmoL),Pd(OAc)₂ (0.021 mmoL, 5 mg), Ph₃P (0.042 mmoL, 11 mg), LiCl (0.84 mmoL,36 mg) and KOAc (4.2 mmoL, 412 mg) were mixed together and flushed withN₂. DMF (10 mL) was added to the reaction and the mixture was heated to100° C. for 6 hrs. The reaction was then cooled down and diluted withEt₂O. The solution was passed through a pad of Celite to remove anyundissolved solids. EtOAc and H₂O were added. The aqueous layer wasexacted 3× with Et₂O. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated to yield a crudebrown oil. The crude material was then purified by column chromatography(silica gel, hexanes:EtOAc 3:1 as eluent) to yield the title compound asa yellow solid.

¹H NMR (CDCl₃, 400 MHz) δ 9.18 (s, br, 1H), 8.02 (s, 1H), 7.78 (s, 1H),3.55 (s, 1H), 3.29 (d, J=10.8 Hz, 1H), 3.04 d, J=10.8 Hz, 1H), 2.45(abq, J=9.6 Hz, 2H), 2.38 (s, 3H), 1.72 (s, 3H), 1.23 (t, J=12.0 Hz, 3H)

MS (m/z): 343 (M+H)⁺, 365 (M+Na)⁺.

Example 792-(5-Bromo-3-methyl-6-trifluoromethyl-1H-indol-2-yl)-1-ethylsulfanyl-propan-2-ol

The compound prepared as in Example 77 (750 mg, 2.05 mmoL), Pd(OAc)₂(0.102 mmoL, 23 mg), Ph₃P (0.204 mmoL, 54 mg), LiCl (2.05 mmoL, 87 mg)and KOAc (10.25 mmoL, 1.01 g) were mixed together and flushed with N₂.DMF (10 mL) was added to the reaction and the mixture was heated to 100°C. for 6 hrs. The reaction was then cooled down and diluted with Et₂O.The solution was passed through a pad of Celite to remove anyundissolved solids. EtOAc and H₂O were added. The aqueous layer wasexacted 3× with Et₂O. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated to yield a crudebrown oil. The crude material was then purified by column chromatography(silica gel, hexanes:EtOAc 3:1 as eluent) to yield the title compound asa dark yellow solid.

¹H NMR (CDCl₃, 400 MHz) δ 8.85 (br, s, 1H), 7.78 (s, 1H), 7.69 (s, 1H),3.52 (s, 1H), 3.25 (s, 1H), 3.02 (d, J=11.0 Hz, 1H), 2.50 (m, J=10.5,2.0 Hz, 2H), 2.30 (s, 3H), 1.68 (s, 3H), 1.18 (t, J=12.5 Hz, 3H)

MS (m/z): 396, 398 (M+H)⁺.

Example 801-Ethylsulfanyl-2-(3-methyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol

The compound prepared as in Example 6 (320 mg, 1.053 mmoL), Pd(OAc)₂(0.526 mmoL, 12 mg), Ph₃P (1.06 mmoL, 28 mg), LiCl (1.053 mmoL, 45 mg)and KOAc (5.265 mmoL, 517 g) were mixed together and flushed with N₂.DMF (10 mL) was added to the reaction and the mixture was heated to 100°C. for 6 hrs. The reaction was then cooled down and diluted with Et₂O.The solution was passed through a pad of Celite to remove anyundissolved solids. EtOAc and H₂O were added. The aqueous layer wasexacted 3× with Et₂O. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated to yield a crudebrown oil. The crude material was then purified by column chromatography(silica gel, hexanes:EtOAc 3:1 as eluent) to yield the title compound asa yellow solid.

¹H NMR (CDCl₃, 400 MHz) δ 9.29 (s, br, 1H), 8.22 (s, 1H), 7.75 (s, 1H),3.58 (br, s, 1H), 3.25 (d, J=10.8 Hz, 1H), 3.05 (d, J=10.8 Hz, 1H), 2.38(m, J=8.5, 7.5 Hz, 2H), 2.32 (s, 3H), 1.68 (s, 3H), 1.16 (t, J=12.0 Hz,3H)

MS (m/z): 363 (M+H)⁺.

Example 81 4-Amino-5-iodo-2-trifluoromethyl-benzonitrile

4-Amino-2-trifluoromethyl-benzonitrile (20.44 g, 109.79 mmoles) andp-toluenesulfonic acid monohydrate (1.05 g, 5.52 mmoles) were dissolvedmethanol (200 mL) and THF (200 mL), and the reaction mixture was stirredunder a nitrogen atmosphere. The reaction vessel was wrapped inaluminium foil, while the solution was stirred for 20 min., thenN-iodosuccinimide (30.41 g, 135.17 mmoles) was added and the reactionwas allowed to stir overnight (16 hrs). The reaction mixture wasconcentrated in vacuo, triturated with hexanes (3×400 mL) andconcentrated to dryness. The crude solid was dissolved in diethyl ether(400 mL), washed with water (3×), the organic extracts were diluted withhexanes (400 mL) and a white solid precipitated. The solid was filteredand dried in a vacuum oven (35° C.@762 Torr) overnight to yield thetitle compound.

¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), δ 7.00 (s, 1H), δ 4.83 (br s,2H)

MS calculated for C₈H₄F₃IN₂: 312.03. found 311 (M−H).

Example 82N-(4-Cyano-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide

4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (8.04 g, 25.77 mmoles) wasdissolved in anhydrous THF (60 mL), stirred under a nitrogen atmosphereand cooled in an ice/brine bath for 20 min. 1.0 M potassiumtert-butoxide in THF (82 mL, 82 mmoles) was added and the reactionmixture was stirred for 20 min. Methanesulfonyl chloride (3.2 mL, 41.18mmoles) was then added and the reaction mixture was stirred at ambienttemperature overnight. The reaction mixture was quenched with 1N HCl (90mL) and extracted with dichloromethane (3×100 mL). The organic extractswere diluted with diethyl ether and a white solid precipitated. Thesolid was filtered, washed and dried to yield the title compound. Thefiltrate was concentrated to a crude orange solid. The compound waspurified by column chromatography (SiO₂, 100% CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H), δ 7.99 (s, 1H), δ 7.10 (s, 1H),δ 3.17 (s, 3H)

MS calculated for C₉H₆F₃IN₂O₂S: 390.12. found 389 (M−H).

Example 83 1,1,1-Trifluoro-2-methyl-but-3-yn-2-ol

To a solution of ethynylmagnesium bromide (60 mL, 0.5 M in THF) cooledto 0° C. under nitrogen was added 1,1,1-trifluoroacetone (2.00 mL, 20.6mmol). The solution was stirred at 0° C. for 1 hour and quenched by thecautious addition of HCl (30 mL, 1 M). After extraction with diethylether, the organic layer was concentrated at 35° C. on a rotaryevaporator and the residue purified by flash chromatography (Silica gel,dichloromethane mobile phase) to yield the title compound as an oil,which was used in the subsequent step without further purification.

Example 842-(2,2,2-Trifluoro-1-hydroxy-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-5-carbonitrile(Compound #329)

N-(4-Cyano-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (1.82 g,4.66 mmoles), dichlorobis(triphenylphosphine)palladium (160 mg, 0.23mmoles) and copper iodide (90 mg, 0.47 mmoles) were suspended inanhydrous THF (20 mL), under a nitrogen atmosphere. Triethylamine (1.30mL, 9.33 mmoles) was added and after 10 min. of stirring,1,1,1-trifluoro-2-methyl-but-3-yn-2-ol was added. The reaction mixturewas stirred overnight at ambient temperature. The reaction mixture wasthen concentrated to a residue, which was purified by columnchromatography (SiO₂, 100% CH₂Cl₂) to yield a semisolid.

The semisolid was dissolved in methanol (20 mL) under vigorouslystirring. Then, 4.0 M sodium hydroxide solution (4.0 mL) was added.After 20 min, the reaction mixture was quenched with 1N HCl (16 mL) andextracted with diethyl ether (3×30 mL). The combined extracts were driedover MgSO₄, filter and concentrated in vacuo to yield the title compoundas a white solid.

MS calculated for C₁₃H₈F₆N₂O: 322.05. found 321 (M−H).

Example 85 (+) and (−) Enantiomers of2-(2,2,2-Trifluoro-1-hydroxy-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-5-carbonitrile(Compounds #334 and #335)

A portion of the title compound prepared as in Example 84 above, wasseparated into its constituent enantiomers by chiral HPLC (Chiralpak AD,isopropyl alcohol/heptane into the less polar dextrorotatory (+)compound, Compound #334 and the more polar levorotatory (−) compoundCompound #335.

Example 86 (+) and (−) Enantiomers of2-(2-Ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-5-carbonitrile(Compounds #218 and #217)

Compound #217 and Compound #218 were prepared by separating2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-5-carbonitrile,the compound prepared as in Example 45, by chiral HPLC (Chiralpak AD,isopropyl alcohol to yield the corresponding less polar dextrorotatory(+) compound, Compound #218 and the more polar levorotatory (−)compound, Compound #217.

Example 87 (−) Enantiomer of2-(2-Ethanesulfonyl-1-hydroxy-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-5-carbonitrile(Compound #222)

The (−) enantiomer of2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-5-carbonitrile,the compound prepared as in Example 86 above (1 equivalent) wasdissolved in ethyl acetate (5 mL/mmol). A separate aqueous solution ofOXONE® (3 equivalents) and Bu₄NHSO₄ (0.3 mol %) (10 mL water/g ofOXONE®) was prepared and the pH of this solution adjusted to about 7 bythe addition of saturated sodium bicarbonate solution. After the pHadjustment, this aqueous solution was added to the ethyl acetatesolution and the resulting biphasic mixture vigorously stirred. After 8hours, an additional 3 equivalents of the pH-adjusted OXONE® solutionwas added and the mixture stirred overnight. Ethyl acetate (10 mL/mmolof sulfide) was added and the aqueous phase was removed. The organicphase was washed with brine, dried over anhydrous Na₂SO₄, concentratedto yield a yellow solid. This crude material (yellow solid) was purifiedusing column chromatography (silica gel, ethyl acetate as eluent) toyield the title compound as a pale yellow solid.

X-Ray crystallographic analysis of this material indicated that theabsolute configuration of the stereocenter is (R).

Example 88 (+) and (−) Enantiomers of2-(2-Ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-3-methyl-6-trifluoromethyl-1H-indole-5-carbonitrile(Compound #234 and #233)

Compound #234 and Compound #233 were prepared by separating2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-3-methyl-6-trifluoromethyl-1H-indole-5-carbonitrile,the compound prepared as in Example 78, by chiral HPLC (Chiralpak AD,30% heptane in isopropyl alcohol into the less polar dextrorotatory (+)compound, Compound #234 and the more polar levorotatory (−) compound,Compound #223.

Example 89 (−) Enantiomer of2-(2-Ethanesulfonyl-1-hydroxy-1-methyl-ethyl)-3-methyl-6-trifluoromethyl-1H-indole-5-carbonitrile(Compound #251)

The (−) enantiomer of2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-3-methyl-6-trifluoromethyl-1H-indole-5-carbonitrile,the compound prepared as in Example 88 above (1 equivalent) wasdissolved in ethyl acetate (5 mL/mmol). A separate aqueous solution ofOXONE® (3 equivalents) and Bu₄NHSO₄ (0.3 mol %) (10 mL water/g ofOXONE®) was prepared and the pH of this solution adjusted to about 7 bythe addition of saturated sodium bicarbonate solution. After the pHadjustment, this aqueous solution was added to the ethyl acetatesolution and the resulting biphasic mixture vigorously stirred. After 8hours, an additional 3 equivalents of the pH-adjusted OXONE® solutionwas added and the mixture stirred overnight. Ethyl acetate (10 mL/mmolof sulfide) was added and the aqueous phase was removed. The organicphase was washed with brine, dried over anhydrous Na₂SO₄, concentratedto yield a yellow solid. This crude material (yellow solid) was purifiedusing column chromatography (silica gel, ethyl acetate as eluent) toyield the title compound as a white solid.

Example 902-(1,2-Dihydroxy-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-5-carbonitrile

To a suspension of2-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-1-methyl-ethyl]-1-methanesulfonyl-6-trifluoromethyl-1H-indole-5-carbonitrile(9.22 g, 0.01935 mole) in methanol (150 mL), a solution of NaOH (4.64 g0.1161 mole) in water (25 mL) was added. The resulting mixture washeated in an oil-bath at 50° C. for 4 hr and then stirred at roomtemperature overnight. To the reaction mixture was then added 1N HCluntil the pH was 3. The aqueous mixture was extracted with EtOAc, theorganic layer was washed with water, brine, then dried over MgSO₄. Thesolvent was stripped off, the residue was triturated with DCM, and theresulting solid collected by filtration to yield the title compound as alight grey solid.

MS m/z (M−H) 283

¹H NMR (300 Hz, DMSO d6). δ1.50 (s. 3H), 2.50 (d, J=1.8 Hz 2H), 4.96 (t,J=5.8 Hz, 1H), 5.50 (s, 1H), 6.55 (s, 1H), 7.87 (s, 1H), 8.29 (s, 1H).

Example 912-[2-(4-Cyano-phenoxy)-1-hydroxy-1-methyl-ethyl]-6-trifluoromethyl-1H-indole-5-carbonitrile(Compound #426)

To a solution of2-(1,2-dihydroxy-1-methyl-ethyl)-6-trifluoromethyl-1-H-indole-5-carbonitrile(209.6 mg, 0.7374 mmol) in dry DMF (4 ml) was added NaH (60 mg, 1.4749mmol, 60% in mineral oil). After the reaction mixture was stirred atroom temperature for 30 min., 4-fluorobenzonitrile (98.15 mg, 0.8115mmol) was added, and the reaction mixture stirred at room temperature.After HPLC indicated the consumption of starting material, the reactionmixture was poured onto water and extracted with ethyl acetate. Theorganic layer was washed with 10% LiCl, brine and dried over MgSO₄.Column chromatography (EtOAc/Hexanes 50%-100%) yielded the title productas a light yellow powder.

MS: no molecular ion.

¹H NMR (400 Hz, MeOD). δ1.77 (s. 3H), 4.85 (s, 2H), 6.66 (s, 1H), 7.09(d, J=9 Hz, 2H), 7.62 (d, J=9 Hz, 2H), 7.87 (s, 1H), 8.13 (s, 1H).

2-[1-Hydroxy-1-methyl-2-(3-nitro-phenoxy)-ethyl]-6-trifluoromethyl-1H-indole-5-carbonitrile,Compound #428

was similarly prepared according to the procedure described in Example91, to yield the product as a brown-yellow solid.

MS: no molecular ion

¹H NMR (400 Hz, DMSO d6). δ1.69 (s. 3H), 4.26 (d, J=9.7 Hz, 2H), 4.33(d, J=9.6 Hz, 2H), 6.06 (s, 1H), 6.65 (s, 1H), 7.11 (m, 1H), 7.37-7.39(m, 1H), 7.62 (t, J=1 Hz, 1H), 7.83-7.86 (m, 1H), 7.88 (s, 1H), 8.33 (s,1H), 12.08 (s, 1H).

2-[2-(4-Cyano-3-trifluoromethyl-phenoxy)-1-hydroxy-1-methyl-ethyl]-6-trifluoromethyl-1H-indole-5-carbonitrile,Compound #429,

was similarly prepared according to the procedure described in Example91, to yield the product as an off-white solid.

MS m/z (M−H) 452

¹H NMR (300 Hz, DMSO d6). δ1.68 (s. 3H), 4.36 (s, 2H), 6.10 (s, 1H),6.67 (s, 1H), 7.44 (m, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.87 (s, 1H), 8.05(d, J=8.5 Hz, 1H), 8.32 (s, 1H).

Example 92 In Vitro Assay Androgen Receptor Filtration Binding Assay(PANVERA)

The assay was run on a 96 well plate with each well filled with a totalreaction volume 150 μL, of a solution containing 5 μmol androgenreceptor LBD (Panvera) or 30 μL of freshly prepared rat cytosol, 0.5 nM[³H] R1881 tracer (NEN), 1.5 μL (10 μM) test compound or vehicle(diluted in 30% DMSO, final concentration of DMSO 0.75%) and 150 μL ofTED buffer. (TED buffer contains 10 mM Tris.HCl pH 7.4, 1 mM sodiummolybdate, 1.5 mM EDTA, 1 mM DTT and 10% (v/v) glycerol.)

On day one, the solution containing receptor, tracer and TED buffer wasdistributed into a 96 well plate. Diluted test compound or controlvehicle was then added to individual wells and the plate incubated at 4°C. overnight.

On day two, to each well was then added 20 μL human γ-globulin (ICN823102), prepared at 25 mg/ml in TE pH 8.0, and 55 μL 40% polyethyleneglycol 8000 (JT Baker U222-08), prepared in TE pH 8.0. The plate wasincubated at 4° C. for 60 minutes. During incubation, the harvester wasrinsed with 10% PEG 8000, prepared in TE pH 8.0, and a GF/C Unifilter-96was pre-wet with 10% PEG. The binding reaction was filtered, theretentate was washed three times with 10% PEG and dried under vacuum fora couple of minutes, then dried at 50° C. for 5 min and the plate wasbottom sealed. Next, 25 μL of Microscint-20 (Packard) was added to thefilter wells and the plate was top sealed. The plate wells were thencounted on a TopCount (Packard).

IC₅₀s were determined by testing serial dilutions of the test compound(usually duplicate ten half-log dilutions starting at 10 μM) in thebinding assay. Counts per well were measured and IC₅₀s determined bylinear regression.

Representative compounds of the present invention were tested forbinding to the androgen receptor according to the procedure describedabove with results as listed in Table A. For compounds tested more thanonce, each result is listed separately in the Table below.

TABLE A Androgen Receptor Binding (Panvera) ID No. IC₅₀ (nM) 1 14000 253000 3 26000 4 7600 5 39000 8 2650 12 39000 19 >100000 20 2350021 >10200 22 >7700 22 >9600 23 54000 25 8800 52 150 53 1967 54 465 54220 55 715 55 635 56 485 56 610 57 141 57 480 58 455 59 4100 60 6750 61440 62 325 63 1550 64 815 65 945 66 2600 67 3000 68 19000 69 1200 70 75075 9100 76 1244 77 1107 78 3556 79 >9500 80 6400 81 15000 82 185 82 20083 160 83 545 84 180 85 460 86 1250 87 350 87 1650 88 5150 89 >960090 >9000 91 1285 92 37000 93 23000 94 15000 95 3000 96 1710 96 820 977400 98 8500 99 5750 100 1155 101 3850 102 665 103 1650 104 930 105 105106 225 107 9400 108 7000 109 2600 110 7700 112 4100 113 5100 114 4900115 7700 116 1750 117 2000 253 335 254 1025 254 920 255 1255 255 3050256 2650 257 5150 258 2450 259 915 260 2050 261 1457 262 >10000

Example 93 Androgen Receptor Binding Using Rat Ventral Prostate Cytosol

Rat Prostate Cytosol Preparation:

Male Sprague Dawley or Wistar rats (Charles River, 200-300 g) were usedfor each preparation. The day before preparing the cytosol, the ratswere castrated using standard surgical procedures.

The rats were euthanized by carbon dioxide asphyxiation. The ratprostates were quickly removed and placed on ice in pre-chilled,pre-weighed 50 mL plastic tubes. No more than five prostates were placedinto one tube. The tubes were then weighed and the prostate tissue wetweights calculated.

To the chilled prostate tissue was then added 1 mL/mg tissue of chilledhomogenization buffer. The homogenization buffer was freshly prepared bymixing 10 mM Tris.HCl, pH 7.4, 1 mM sodium molybdate, 1.5 mM EDTA, 1 mMdithiothreitol, 10% (v/v) glycerol and 1% protease inhibitor cocktail(Sigma P 8340).

The prostate tissue was homogenized in a cold room using a pre-chilledPolytron PT3000 homogenizer (Brinkmann). Homogenization was performed ata speed setting of 20, three times for 10 sec bursts. The tubescontaining the prostate tissue was kept on ice while homogenizing. Thehomogenate was allowed to rest on ice for 20 sec between bursts.

The homogenate was then placed into pre-chilled 3 mL polycarbonateultracentrifuge tubes and centrifuged in the TLA-100 rotor of a TL-100ultracentrifuge for 12 min at 100,000 rpm at 4° C. The resultingsupernatant was stored in 1 mL aliquots at −80° C. until needed.

Binding to the androgen receptor was determined according to theprotocol described in Example 86 using the above prepared rat cytosol.

% Inhibition was determined by testing dilutions of the test compound(usually duplicates of 10 μM) in the binding assay. Counts per well weremeasured and percents of inhibition determined. Androgen receptorbinding IC₅₀s were determined by testing serial dilutions of the testcompound (usually duplicate ten half-log dilutions starting at 10 μM) inthe binding assay. Counts per well were measured and IC₅₀s determined bylinear regression.

Representative compounds of the present invention were tested forbinding to the androgen receptor according to the procedure describedabove with results as listed in Table B. For compounds tested more thanonce, each result is listed separately in the Table below.

TABLE B Androgen Receptor Binding (Rat Cytosol) ID No. % InhibitionConcentration IC₅₀ (nM) 1 22 1000 nM 2 2.5 1000 nM 3 6.6 1000 nM 4 10.751000 nM 5 5.5 1000 nM 8 −2 1000 nM 12 47.5 1000 nM 18 38 3000 nM 17 883000 nM 19 −55 1000 nM 20 −28.5 1000 nM 21 −41.5 1000 nM 22 5.325 1000nM 22 −12.2 1000 nM >7700 23 −1.5 1000 nM 6000 24 2 1000 nM 25 −83.51000 nM 26 21 1000 nM 27 14 1000 nM 3100 28 −3.4 1000 nM 7000 29 −1.81000 nM 4700 30 −7.7 1000 nM 4100 31 20 1000 nM 4050 32 34 1000 nM 4300033 11 1000 nM 29000 34 18 1000 nM 5700 35 −19 1000 nM 4200 36 −34 1000nM >100000 37 25 1000 nM 3600 38 16 1000 nM 8800 39 6 1000 nM >6100 40−2.5 1000 nM 3800 41 20 1000 nM 2300 42 23 1000 nM 7100 43 5.8 1000 nM9100 47 81 3000 nM 49 48 3000 nM 52 94.5 1000 nM 79 53 9.75 1000 nM 545.5 1000 nM 55 180 55 5.5 1000 nM 56 38.5 1000 nM 57 100 57 78.5 1000 nM58 79.5 1000 nM 59 67.5 1000 nM 220 60 44.5 1000 nM >10000 61 73 1000 nM62 69 1000 nM 63 47.5 1000 nM 64 61.5 1000 nM 65 47.5 1000 nM 66 −121000 nM 67 25.5 1000 nM 68 36 1000 nM 69 31 1000 nM 70 33.65 1000 nM 7513.15 1000 nM 76 −30.5 1000 nM 77 −9.25 1000 nM 78 16.56 1000 nM 79 48.51000 nM 80 −24.95 1000 nM 81 5.2 1000 nM 82 69.75 1000 nM 640 82 83 1000nM 83 69 1000 nM 83 120 84 86 1000 nM 240 85 78.5 1000 nM 110 85 89 1000nM 86 72.5 1000 nM 240 87 85 1000 nM 87 61.5 1000 nM 120 88 −17.45 1000nM 90 −2.5 1000 nM 91 36 1000 nM 92 14.68 1000 nM 93 35 1000 nM 94 21.81000 nM 95 56.5 1000 nM 96 74 1000 nM 96 59 1000 nM 97 25 1000 nM 98 −311000 nM 99 8.5 1000 nM 100 80 1000 nM 101 −24.94 1000 nM 102 73.5 1000nM 140 104 94.5 1000 nM 104 110 3000 nM 105 61.5 1000 nM 98 106 63 1000nM 300 107 1.5 1000 nM 108 17.5 1000 nM 109 49 1000 nM 110 58.5 1000 nM112 39.5 1000 nM 113 −17.5 1000 nM 113 75.5 1000 nM 114 61 1000 nM 11554.5 1000 nM 1300 116 28.4 1000 nM 117 32.5 1000 nM 118 80.5 3000 nM 120130 3000 nM 121 86 3000 nM 122 83.5 3000 nM 123 77 3000 nM 123 15 3000nM 124 66.5 3000 nM 124 4.4 3000 nM 125 21 3000 nM 126 −30 3000 nM 127−35 3000 nM 127 36 3000 nM 128 25 3000 nM 129 39.5 3000 nM 130 32.553000 nM 131 120 3000 nM 132 64.5 3000 nM 133 54 3000 nM 135 130 3000 nM136 38 3000 nM 137 57.5 3000 nM 138 110 3000 nM 139 87.5 3000 nM 13931.5 3000 nM 140 47 3000 nM 141 −4.5 3000 nM 142 92 3000 nM 143 14 3000nM 144 79 3000 nM 145 58 3000 nM 147 68 3000 nM 148 94 3000 nM 149 943000 nM 149 77 3000 nM 150 120 3000 nM 151 100 3000 nM 152 97 3000 nM154 29 3000 nM 155 −6.1 3000 nM 156 66 3000 nM 156 67 3000 nM 158 523000 nM 159 93 3000 nM 160 65 3000 nM 161 39 3000 nM 162 0.69 3000 nM164 52 3000 nM 165 52 3000 nM 168 41 3000 nM 169 62 3000 nM 170 80 3000nM 171 18 3000 nM 171 320 173 32 3000 nM 176 90 3000 nM 253 33.5 1000 nM254 670 254 41 1000 nM 255 26 1000 nM 258 35.4 1000 nM 261 14.05 1000 nM262 −8.4 1000 nM 265 93.5 3000 nM 266 12.4 3000 nM 267 79 3000 nM 267 283000 nM 268 −3.3 3000 nM

Example 94 COS-7 Whole-Cell Androgen Receptor Binding Assay, AdenovirusTransduction

Day One:

COS-7 cells were plated in 96-well plates at 20,000 cells per well, in asolution of DMEM/F12 (GIBCO) containing 10% (v/v) charcoal-treated fetalbovine serum (Hyclone) and lacking phenol red. The cells were thenincubated overnight at 37° C. in 5% (v/v) humidified CO₂.

Day Two:

Test compound solutions were prepared by diluting the test compound in100% (v/v) DMSO, if necessary. Each dilution yielded a solution whichwas 625× the final desired test concentration.

Next, 1 mL of DMEM/F12 lacking phenol red was pipetted into each of thewells of a 2-mL 96-well assay block. Then 4 μL of the 625× test compounddilutions were pipetted into each well of the assay block. The wellswere carefully mixed by pipette.

In a 15 mL or 50 mL sterile centrifuge tube, a 2.5 nM dilution oftritiated methyl-trienolone in DMEM/F12 lacking phenol red ([³H]R1881;Perkin-Elmer) was prepared.

In a 15 mL or 50 mL sterile centrifuge tube, a dilution in DMEM/F12 ofthe adenovirus AdEasy+rAR at a moi of 1:50 per well was prepared.

The medium was removed from the 96-well plates by inversion and theplates dried very briefly, inverted, on a sterile towel. As soon aspossible after medium removal, 40 μL of the diluted test compound wasadded to each well, in duplicate. To each well was then added 40 μL ofthe 2.5 nM [³H]R1881 and 20 μL of the diluted adenovirus. The plateswere then incubated for 48 hours at 37° C. in 5% (v/v) humidified CO₂.

Day Four:

The medium was removed from the above incubated plates by inversion anddried. Each well was then washed with 0.35 mL of 1×PBS. The PBS was thenremoved from the plates by inversion and the plates dried.

To each well was then added 50 μL of 0.5% (v/v) Triton X-100 (Sigma) in1×PBS and the plates placed on a rotary shaker for 5 min. The contentsof each well were then transferred to an OptiPlate-96 (Packard)scintillation plate. To each well was then added 0.2 mL of Microscint-20(Packard) and the wells counted on a TopCount (Packard).

Percent inhibition was determined by testing dilutions of the testcompound (usually duplicates of 10 μM) in the binding assay. Counts perwell were measured and percents of inhibition determined. Androgenreceptor binding IC₅₀s were determined by testing serial dilutions ofthe test compound (usually duplicate ten half-log dilutions starting at10 μM) in the binding assay. Counts per well were measured and IC₅₀sdetermined by linear regression.

Representative compounds of the present invention were tested forbinding to the androgen receptor according to the procedure describedabove with results as listed in Table C. Unless otherwise noted, COSbinding % inhibition was determined using a concentration of 3000 nM.For compounds tested more than once, each result is listed separately inthe Table below.

TABLE C COS Binding ID No. % Inhibition IC₅₀ (nM) 10 >3000 11 >300017 >1500 47 78 >1000 49 30 >3000 50 7 51 54 104 94 1000 118 >1500 11862 >1300 120 86 205 121 72 >1800 122 66 >1600 123 82 >1800 123 32 >3000124 54 >880 124 11 >3000 125 30 126 29 127 41 127 74 >1200 128 21 >1500129 10 130 −8 131 84 >1600 132 8.7 >3000 133 65 >1500 134 >10000 135 98320 136 4.8 526.7 137 73 >1500 138 78 317 139 94 63 139 97 252.5 14051.5 >1500 141 42 141 >3000 142 90 220 143 68 >1500 144 375 145 84.736.7 147 6.1 >3000 148 32 >2400 149 63 780 149 78 >790 150 81 165 150 74626.5 151 >970 151 55 2185.5 152 39 108 154 50 155 35 156 42 >1000 15652 >1000 158 62 160 158 56 550 159 90 240 160 84 250 161 20 162 56 16468 >1000 165 69 >3000 166 3000 167 >3000 168 60 >3000 169 90 48 17067 >3000 171 92 145 171 94 173 17 >3000 175 >3000 176 75 1500 177 90 88180 24 185 92 61 189 100 280 190 100 292 191 65 840 192 86 82 194 80 320196 53 197 86 >3000 198 55 199 82 310 200 97 1000 201 86 340 202 50 206−40 207 −35 207 39 208 −26 208 −22 209 61 1843.3 211 43 212 86 98 21371 >600 214 >3000 217 792.4 217 38 >3000 217 61 493.1 217 69 149.1 2196.2 220 34 222 42 1584 225 82 141.6 230 49 231 73 665 231 78 >3000 23395 45.6 233 81 234 71 539.4 235 78 519.7 236 83 105 240 48 241 48 242 92305.1 244 32 245 47 246 70 616.2 247 90 60.7 248 24 250 79 251 85 220252 68 >3000 265 86 585 266 38 267 75 264 267 79 89.6 268 42

Example 95 L929 Androgen Receptor Functional Assay, AdenovirusTransduction

Day One:

L929 cells were plated in 96-well plates at 20,000 cells per well, inDMEM/F12 (GIBCO) containing 10% (v/v) charcoal-treated fetal bovineserum (Hyclone) and lacking phenol red. The plates were then incubatedovernight at 37° C. in 5% (v/v) humidified CO₂.

Day Two:

Test compound dilutions were prepared in 100% (v/v) DMSO, if necessary.Each dilution was made to 1250× the final desired assay concentration.

First, 2 mL of DMEM/F12 lacking phenol red was pipetted into the wellsof a 2-mL 96-well assay block. Next, 4 μL of the 1250× test compounddilutions were pipetted into each well of the assay block. The mixtureswithin the well were then carefully mixed by pipette.

In a 15 mL or 50 mL sterile centrifuge tube, a 2.5 nM (2.5×) dilution ofR1881 (methyl-trienolone) in DMEM/F12 lacking phenol red was prepared.

In a second 15 mL or 50 mL centrifuge tube a solution containing anequal volume of DMEM to the first and an equal volume of 100% (v/v) DMSOto the volume of R1881 used in the first tube was prepared.

In a 15 mL or 50 mL sterile centrifuge tube, a dilution in DMEM/F12 ofthe adenovirus AdEasy+rAR at an moi of 1:500 per well was prepared.

The medium was removed from the 96-well plates by inversion and dried,inverted, very briefly. As soon as possible after medium removal, 40 μLof the diluted unlabeled test compound was added to each well, induplicate. To each well designated for antagonist testing was added 40μL of the 2.5 nM R1881 dilution to the wells for antagonist testing. Toeach well designated for agonist testing was added 40 μL of the DMSOdilution. Then 20 μL of the diluted adenovirus were added to all wells.The plates were incubated for 48 hours at 37° C. in 5% (v/v) humidifiedCO₂.

Day Four:

To each well was added 100 μL of Steady-Glo luciferase assay substrate(Promega) and the plates were placed on a rotary shaker for 1 min. Theplates were then incubated at room temperature in the dark for one hour.The contents of each well were then transferred to a white microtiterplate (Packard) and read on a Luminoskan Ascent (Thermo Lab Systems).

L929 AR percent activity was determined by testing dilutions of the testcompound using a concentration of 3000 nM unless otherwise noted. L929percent inhibition was determined by testing dilutions of the testcompound using a concentration of 3000 nM. EC₅₀s and IC₅₀s weredetermined by testing serial dilutions of the test compound (usuallyduplicate ten half-log dilutions starting at 10 μM). Luciferase activityper well were measured and EC₅₀s and IC₅₀s determined by linearregression.

Representative compounds of the present invention were tested forfunctional activity at the androgen receptor according to the proceduredescribed above with results as listed in Table D. For compounds testedmore than once, each result is listed separately in the Table below.

TABLE D L929 ANDROGEN RECEPTOR FUNCTIONAL ASSAY ID No. % Activity %Inhibition EC₅₀ (nM) IC₅₀ (nM) 47 2 75 49 2 8 50 2 36 51 2 −39 104 9 18118 −2 @ 8000 nM 63 >8000 3067.5 120 −5 44 121 −4 54 122 10 35 123 −4 1123  1 @ 8000 nM 30 124 −4 20 124 −4 99 125 −5 28 126 −5 25 127 −5 66127 −5 32 128 −4 44 129 −5 −8 130 −5 46 131 −5 −4 132 −5 48 133 −4 19135 0 40 136 0 75 137 0 77 138 0 19 139 0 43 139 1 91 140 0 78 141 0 42142 0 78 143 0 67 144 0 82 145 1 94 147 0 43 148 0 77 149 2 77 150  0 @8000 nM >8000 303.4 151 −1 @ 8000 nM >8000 533.4 154 2 7 155 2 −2 156 235 156 2 23 158 3 21 158 2 29 159 2 82 160 1 76 161 2 24 162 2 64 164 271 165 1 100 168 3 26 169 2 98 170 2 67 171 −1 @ 8000 nM 101 >8000 366171 11 70 173 2 40 176 3 81 177 2 89 180 2 −11 185 2 97 189 3 85 190 197 191 2 −6 192 8 89 194 2 40 196 13 −119 197 2 −26 198 7 24 199 2 59200 1 96 201 2 83 202 1 21 206 5 88 207 1 101 207 −1 101 >8000 492.2 2081 24 209 −3 @ 8000 nM 87 >8000 372.4 211 −1 88 212 −3 101 213 −1 @ 8000nM 92 >8000 371.8 217  0 @ 8000 nM 87 >8000 969.4 217 414.7 217 5 80 810218 0 62 219 −3 103 220 −3 103 221 −1 23 222  0 @ 8000 nM 61 >80002406.7 223  0 @ 8000 nM 100 >8000 277.4 225 1 97 228.9 230 0 45 231 0 753184.4 231 −1 37 233 0 97 69.2 234 −1 99 214.6 235 3 95 1842.7 236 2 103821.3 240 0 47 251 −1 90 200 252 1 65 3100 265 −1 65 266 −4 65 267 −5−13 267 0 19 268 9 83

Example 96 Ventral Prostate and Seminal Vesicle Weight In Vivo Assay

Immature (approximately 50 g) castrated male Sprague Dawley rats(Charles River) were treated once daily for five days with test compound(usually given orally at 40 mg/kg in a volume of 0.3 mL, in 30%cyclodextrin or 0.5% methylcellulose vehicle) and with testosteronepropionate (given subcutaneously by injection at the nape of the neck at2 mg/kg, in a volume of 0.1 mL in sesame oil). On the sixth day, therats were euthanized by asphyxiation in carbon dioxide. Ventralprosatates and seminal vesicles were removed and their wet weightsdetermined. Test compound activity was determined as the percentinhibition of testosterone-enhanced tissue weights, with avehicle-treated control group set to zero percent and a testosteronealone-treated control group set to 100%.

A test compound was said to be “active” if the non weight adjustedprostate weight was ≦40 mg or the % Inhibition prostate weight, bodyweight adjusted was ≧40%@2 mg/day dosage. ID₅₀'s, if determined, of ≦15mg/day also indicated an “active” compound.

Compounds #136, 139, 140, 142, 143, 159, 165, 167, 169, 170, 171, 171,175, 176, 177, 181, 185, 190, 191, 192, 202, 205, 206, 207, 208, 209,212, 213, 217, 222, 223, 224, 225, 230, 231, 232, 233, 236, 237, 243,244, 250, 251, 252, 275, 276, 277, 278, 284, 288, 289, 291, 319, 327,329, 330, 331, 332, 333, 334, 335, 344, 345, 347, 349, 354, 357 and 404were tested according to the procedure described above and determined tobe “active”.

Compounds #6, 7, 9, 10, 11, 13, 14, 15, 17, 18, 47, 49, 50, 51, 85, 104,113, 118, 123, 124, 126, 127, 129, 131, 133, 134, 135, 137, 138, 141,146, 152, 153, 155, 156, 158, 160, 161, 162, 164, 166, 168, 173, 180,189, 194, 196, 197, 198, 199, 200, 201, 204, 218, 219, 220, 221, 228,234, 235, 240, 241, 242, 245, 247, 266, 267, 268, 269, 270, 273, 274,279, 280, 281, 282, 285, 285, 287, 290, 294, 295, 317, 318, 322, 323,324, 325, 326, 353, 397, 403, 405, 407, 408, 410, 411, 412, 413, 414,415, 426, 428, 429, 445 and 446 were tested according to the proceduredescribed above and determined to be “inactive”. Note that while certainof these compounds may or may not have shown an effect on prostateand/or vesicle weight, they are listed herein as “inactive” as they didnot meet the specified criteria defined above.

Example 97

As a specific embodiment of an oral composition, 50 mg of Compound #222prepared as described above is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size O hardgel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of formula (III)

wherein

is a six membered heteroaryl ring structure containing two nitrogenatoms; Y is NR¹; R¹ is selected from the group consisting of hydrogen,lower alkyl, fluorinated lower alkyl, —SO₂-(lower alkyl), —SO₂-phenyl,—SO₂-tolyl, —(CH₂)-(fluorinated lower alkyl), -(lower alkyl)-CN, -(loweralkyl)-C(O)—O-(lower alkyl), -(lower alkyl)-O-(lower alkyl) and -(loweralkyl)-S(O)₀₋₂-(lower alkyl); R⁴ is selected from the group consistingof hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl andcyano; wherein the lower alkyl, lower alkenyl or lower alkynyl isoptionally substituted on the terminal carbon atom with —Si(loweralkyl)₃; a is an integer from 0 to 4; R⁵ is selected from the groupconsisting halogen, hydroxy, carboxy, lower alkyl, halogen substitutedlower alkyl, lower alkoxy, halogen substituted lower alkoxy, cyano,nitro, amino, lower alkylamino, di(lower alkyl)amino, —C(O)-(loweralkyl), —C(O)-(lower alkoxy), —C(O)—N(R^(A))₂, —S(O)₀₋₂-(lower alkyl),—SO₂—N(R^(A))₂, —N(R^(A))—C(O)-(lower alkyl), —N(R^(A))—C(O)-(halogensubstituted lower alkyl) and aryl; wherein each R^(A) is independentlyselected from hydrogen or lower alkyl; wherein the aryl is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, carboxy, lower alkyl, halogen substituted lower alkyl,lower alkoxy, halogen substituted lower alkoxy, cyano, nitro, amino,lower alkylamino or di(lower alkyl)amino; b is an integer from 0 to 1; cis an integer from 0 to 1; R⁷ is selected from the group consisting ofhydrogen, lower alkyl and —Si(lower alkyl)₃; R² is selected from thegroup consisting of hydrogen, lower alkyl, halogen substituted loweralkyl and —(CH₂)₁₋₄—Z—R⁶; R³ is selected from the group consisting oflower alkyl, halogen substituted lower alkyl and —(CH₂)₁₋₄—Z—R^(6;)wherein each Z is independently selected from the group consisting of—S(O)₀₋₂—, —O—, —O—C(O)—, —NH— and —N(lower alkyl)-; wherein each R⁶ isindependently selected from the group consisting of lower alkyl, halogensubstituted lower alkyl lower alkenyl, aryl, aralkyl, biphenyl,cycloalkyl, cycloalkyl-(lower alkyl), heteroaryl and heteroaryl-(loweralkyl); wherein the cycloalkyl, aryl or heteroaryl group, whether aloneor part of a substituent group is optionally substituted with one ormore substituents independently selected from halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, cyano,nitro, amino, lower alkylamino, di(lower alkyl)amino, —S(O)₀₋₂-(loweralkyl) and —SO₂—N(R^(A))₂; provided that when Z is O, NH or N(loweralkyl) then Z is other than lower alkenyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound as in claim 1 wherein b and c areeach
 0. 3. A compound as in claim 1 wherein R² is —(CH₂)₁₋₄—Z—R⁶ andwherein Z is selected from the group consisting of —S—, —SO— and —SO₂—.4. A compound as in claim 1 wherein R² is (CH₂)₁₋₄—Z—R⁶ and wherein Z isselected from the group consisting of —O— and —O—C(O)—.
 5. A compound asin claim 1 wherein R² is (CH₂)₁₋₄—Z—R⁶ and wherein Z is selected fromthe group consisting of —NH— and —N(lower alkyl)-.
 6. A compound as inclaim 1

is a six membered heteroaryl ring structure containing two nitrogenatoms; Y is NR¹; R¹ is selected from the group consisting of hydrogen,lower alkyl, fluorinated lower alkyl, -(lower alkyl)-CN, (loweralkyl)-O-(lower alkyl), (lower alkyl)-S(O)₀₋₂-(lower alkyl) and—SO₂-(lower alkyl); R⁴ is selected from the group consisting ofhydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl and cyano;wherein the lower alkyl, the lower alkenyl or the lower alkynyl isoptionally substituted on the terminal carbon atom with —Si(loweralkyl)₃; a is an integer from 0 to 3; R⁵ is selected from the groupconsisting of halogen, lower alkyl, halogen substituted lower alkyl,lower alkoxy, halogen substituted lower alkoxy, cyano, nitro, amino,(lower alkyl)amino, di(lower alkyl)amino, —C(O)-(lower alkyl),—C(O)-(lower alkoxy), —NH—C(O)-(lower alkyl), —NH—C(O)-(trifluoromethyl)and phenyl; wherein the phenyl is optionally substituted with one to twosubstituents independently selected from halogen, hydroxy, carboxy,lower alkyl, trifluoromethyl, lower alkoxy, trifluoromethoxy, cyano,nitro, amino, lower alkylamino or di(lower alkyl)amino; b is an integerfrom 0 to 1; c is an integer from 0 to 1; R⁷ is selected from the groupconsisting of hydrogen, lower alkyl and —Si(lower alkyl)₃; R² isselected from the group consisting of hydrogen, lower alkyl, halogensubstituted lower alkyl and —(CH₂)—Z—R⁶; R³ is selected from the groupconsisting of lower alkyl, halogen substituted lower alkyl,—(CH₂)₀₋₂—Z—R⁶; wherein each Z is independently selected from the groupconsisting of —S(O)₀₋₂—, —O— and —O—C(O)—; wherein each R⁶ isindependently selected from the group consisting of lower alkyl, halogensubstituted lower alkyl, lower alkenyl, cycloalkyl, aryl, aralkyl,biphenyl, heteroaryl and heteroaryl-(lower alkyl)-; wherein the aryl orheteroaryl, whether alone or part of a substituent group is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, carboxy, cyano, nitro, amino, (lower alkyl)amino,di(lower alkyl)amino, lower alkyl, halogen substituted lower alkyl,lower alkoxy or —S(O)₀₋₂-(lower alkyl); provided that when Z is O, thenR¹ is other than lower alkenyl; or a pharmaceutically acceptable saltthereof.
 7. A compound as in claim 1 wherein Y is NR¹; R¹ is selectedfrom the group consisting of hydrogen, lower alkyl, fluorinated loweralkyl, —SO₂-(lower alkyl), —(CH₂)-(fluorinated lower alkyl), (loweralkyl)-CN, -(lower alkyl)-C(O)—O-(lower alkyl), -(lower alkyl)-O-(loweralkyl) and -(lower alkyl)-S(O)₀₋₂-(lower alkyl); R1 is selected from thegroup consisting of hydrogen, halogen, lower alkyl, lower alkenyl, loweralkynyl and cyano; wherein the lower alkyl, lower alkenyl or loweralkynyl is optionally substituted on the terminal carbon atom with—Si(lower alkyl)₃; a is an integer from 0 to 4; R⁵ is selected from thegroup consisting halogen, hydroxy, carboxy, lower alkyl, halogensubstituted lower alkyl, lower alkoxy, halogen substituted lower alkoxy,cyano, nitro, amino, lower alkylamino, di(lower alkyl)amino,—C(O)-(lower alkyl), —C(O)-(lower alkoxy), —C(O)—N(R^(A))₂,S(O)O₀₋₂-(lower alkyl),SO₂—N(R^(A))₂, —N(R^(A))—C(O)-(lower alkyl),—N(R^(A))—C(O)-(halogen substituted lower alkyl) and aryl; wherein eachR^(A) is independently selected from hydrogen or lower alkyl; whereinthe aryl is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, carboxy, lower alkyl,halogen substituted lower alkyl, lower alkoxy, halogen substituted loweralkoxy, cyano, nitro, amino, lower alkylamino or di(lower alkyl)amino; bis an integer from 0 to 1; c is an integer from 0 to 1; R⁷ is selectedfrom the group consisting of hydrogen, lower alkyl and —Si(loweralkyl)₃; R² is selected from the group consisting of hydrogen, loweralkyl and halogen substituted lower alkyl; R³ is —(CH₂)₁₋₄—Z—R⁶; Z is—S(O)₀₋₂—; R⁶ is selected from the group consisting of lower alkyl,halogen substituted lower alkyl lower alkenyl, aryl, aralkyl, biphenyl,cycloalkyl, cycloalkyl-(lower alkyl), heteroaryl and heteroaryl-(loweralkyl); wherein the cycloalkyl, aryl or heteroaryl group, whether aloneor part of a substituent group is optionally substituted with one ormore substituents independently selected from halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, cyano,nitro, amino, lower alkylamino, di(lower alkyl)amino, —S(O)₀₋₂-(loweralkyl) and —SO₂—N(R^(A))₂; or a pharmaceutically acceptable saltthereof.
 8. A compound of formula (III)

wherein

is a six membered heteroaryl ring structure containing-two nitrogenatoms; Y is NR¹; R¹ is selected from the group consisting of hydrogen,lower alkyl, fluorinated lower alkyl, —SO₂-(lower alkyl),—(CH₂)-(fluorinated lower alkyl), (lower alkyl)-CN, -(loweralkyl)-C(O)—O-(lower alkyl), -(lower alkyl)-O-(lower alkyl) and -(loweralkyl)-S(O)₀₋₂-(lower alkyl); R¹ is selected from the group consistingof hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl andcyano; wherein the lower alkyl, lower alkenyl or lower alkynyl isoptionally substituted on the terminal carbon atom with —Si(loweralkyl)₃; a is an integer from 0 to 4; R⁵ is selected from the groupconsisting halogen, hydroxy, carboxy, lower alkyl, halogen substitutedlower alkyl, lower alkoxy, halogen substituted lower alkoxy, cyano,nitro, amino, lower alkylamino, di(lower alkyl)amino, —C(O)-(loweralkyl), —C(O)-(lower alkoxy), —C(O)—N(R^(A))₂, S(O)₀₋₂-(lower alkyl),SO₂—N(R^(A))₂, —N(R^(A))—C(O)-(lower alkyl), —N(R^(A))—C(O)-(halogensubstituted lower alkyl) and aryl; wherein each R^(A) is independentlyselected from hydrogen or lower alkyl; wherein the aryl is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, carboxy, lower alkyl, halogen substituted lower alkyl,lower alkoxy, halogen substituted lower alkoxy, cyano, nitro, amino,lower alkylamino or di(lower alkyl)amino; b is an integer from 0 to 1; cis an integer from 0 to 1; R⁷ is selected from the group consisting ofhydrogen, lower alkyl and —Si(lower alkyl)₃; R² is selected from thegroup consisting of hydrogen, lower alkyl, halogen substituted loweralkyl and —(CH₂)₁₋₄—Z—R⁶; R³ is selected from the group consisting oflower alkyl, halogen substituted lower alkyl and —(CH₂)₁₋₄—Z—R⁶; whereineach Z is independently selected from the group consisting of —S(O)₀₋₂—,—O—, —O—C(O)—, —NH— and —N(lower alkyl)-; wherein each R¹ isindependently selected from the group consisting of lower alkyl, halogensubstituted lower alkyl lower alkenyl, aryl, aralkyl, biphenyl,cycloalkyl, cycloalkyl-(lower alkyl), heteroaryl and heteroaryl-(loweralkyl); wherein the cycloalkyl, aryl or heteroaryl group, whether aloneor part of a substituent group is optionally substituted with one ormore substituents independently selected from halogen, hydroxy, carboxy,lower alkyl, halogen substituted lower alkyl, lower alkoxy, cyano,nitro, amino, lower alkylamino, di(lower alkyl)amino, —S(O)₀₋₂-(loweralkyl) and —SO₂—N(R^(A))₂; provided that when Z is O, NH or N(loweralkyl) then Z is other than lower alkenyl; or a pharmaceuticallyacceptable salt thereof.